Fused heterocyclic imido and amido compounds

ABSTRACT

Disclosed are fused cyclic compounds, method of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds of formula 
                         
Also disclosed are fused heterocyclic imido and amido compounds of formula
 
                         
and stereoisomers thereof. The groups G, L, Z 1 , Z 2 , Q 1 , Q 2 , A 1 , A 2 , Y′, and W′ are defined herein.

This application is a divisional application of U.S. application Ser.No. 10/322,077, filed Dec. 18, 2002, now abandoned, which is acontinuation-in-part of U.S. application Ser. No. 10/025,116, filed Dec.19, 2001, now abandoned, which is a continuation-in-part of U.S.application Ser. No. 09/885,381, filed Jun. 20, 2001, now abandoned, andalso a continuation-in-part of U.S. application Ser. No. 09/885,827,filed Jun. 20, 2001, now U.S. Pat. No. 6,960,474, which applications areincorporated herein by reference in their entirety, wherein U.S.application Ser. No. 09/885,381 further claims the benefit ofprovisional Application No. 60/233,519, filed Sep. 19, 2000, andprovisional Application No. 60/284,730, filed Apr. 18, 2001, andprovisional Application No. 60/284,438, filed Apr. 18, 2001, whichprovisional applications are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to fused cyclic compounds, to methods ofusing such compounds in the treatment of nuclear hormonereceptor-associated conditions such as cancer, and to pharmaceuticalcompositions containing such compounds.

BACKGROUND OF THE INVENTION

Nuclear hormone receptors (NHR's) constitute a large super-family ofligand-dependent and sequence-specific transcription factors. Members ofthis family influence transcription either directly, through specificbinding to the promoter target genes (Evans, in Science 240: 889-895(1988)), or indirectly, via protein-protein interactions with othertranscription factors (Jonat et al., Cell 62: 1189-1204 (1990), Schueleet al., Cell 62: 1217-1226 (1990), and Yang-Yen et al., Cell 62:1205-1215 (1990)). The nuclear hormone receptor super-family (also knownin the art as the “steroid/thyroid hormone receptor super-family”)includes receptors for a variety of hydrophobic ligands, includingcortisol, aldosterone, estrogen, progesterone, testosterone, vitamin D3,thyroid hormone and retinoic acid (Evans, 1988, supra). In addition tothese conventional nuclear hormone receptors, the super-family containsa number of proteins that have no known ligands, termed orphan nuclearhormone receptors (Mangelsdorf et al., Cell 83: 835-839 (1995), O'Malleyet al., Mol. Endocrinol. 10: 1293 (1996), Enmark et al., Mol.Endocrinol. 10, 1293-1307 (1996) and Giguere, Endocrin. Rev. 20, 689-725(1999)). The conventional nuclear hormone receptors are generallytransactivators in the presence of ligand, and can either be activerepressors or transcriptionally inert in the absence of ligand. Some ofthe orphan receptors behave as if they are transcriptionally inert inthe absence of ligand. Others, however, behave as either constitutiveactivators or repressors. These orphan nuclear hormone receptors areeither under the control of ubiquitous ligands that have not beenidentified, or do not need to bind ligand to exert these activities.

In common with other transcription factors, the nuclear hormonereceptors have a modular structure, being comprised of three distinctdomains: an N-terminal domain of variable size containing atranscriptional activation function AF-1, a highly conserved DNA bindingdomain and a moderately conserved ligand-binding domain. Theligand-binding domain is not only responsible for binding the specificligand but also contains a transcriptional activation function calledAF-2 and a dimerisation domain (Wurtz et al., Nature Struc. Biol. 3,87-94 (1996), Parker et al., Nature Struc. Biol. 3, 113-115 (1996) andKumar et al., Steroids 64, 310-319 (1999)). Although the overall proteinsequence of these receptors can vary significantly, all share both acommon structural arrangement indicative of divergence from an ancestralarchetype, and substantial homology (especially, sequence identity) atthe ligand-binding domain.

The steroid binding nuclear hormone receptors (SB-NHR's) comprise asub-family of nuclear hormone receptors. These receptors are related inthat they share a stronger sequence homology to one another,particularly in the ligand binding domain (LBD), than to the othermembers of the NHR super-family (Evans, 1988, supra) and they allutilize steroid based ligands. Some examples of this sub-family of NHR'sare the androgen receptor (AR), the estrogen receptor (ER), theprogesterone receptor (PR), the glucocorticoid receptor (GR), themineralocorticoid receptor (MR), the aldosterone receptor (ALDR) and thesteroid and xenobiotic receptor (SXR) (Evans et al., WO 99/35246). Basedon the strong sequence homology in the LBD, several orphan receptors mayalso be members of the SB-NHR sub-family.

Consistent with the high sequence homology found in the LBD for each ofthe SB-NHR's, the natural ligands for each is derived from a commonsteroid core. Examples of some of the steroid based ligands utilized bymembers of the SB-NHR's include cortisol, aldosterone, estrogen,progesterone, testosterone and dihydrotestosterone. Specificity of aparticular steroid based ligand for one SB-NHR versus another isobtained by differential substitution about the steroid core. Highaffinity binding to a particular SB-NHR, coupled with high levelspecificity for that particular SB-NHR, can be achieved with only minorstructural changes about the steroid core (e.g., Waller et al., Toxicol.Appl. Pharmacol. 137, 219-227 (1996) and Mekenyan et al., Environ. Sci.Technol. 31, 3702-3711 (1997), binding affinity for progesterone towardsthe androgen receptor as compared to testosterone).

Numerous synthetically derived steroidal and non-steroidal agonists andantagonists have been described for the members of the SB-NHR family.Many of these agonist and antagonist ligands are used clinically in manto treat a variety of medical conditions. RU486 is an example of asynthetic agonist of the PR, which is utilized as a birth control agent(Vegeto et al., Cell 69: 703-713 (1992)), and Flutamide is an example ofan antagonist of the AR, which is utilized for the treatment of prostatecancer (Neri et al, Endo. 91, 427-437 (1972)). Tamoxifen is an exampleof a tissues specific modulator of the ER function, that is used in thetreatment of breast cancer (Smigel, J. Natl. Cancer Inst. 90, 647-648(1998)). Tamoxifen can function as an antagonist of the ER in breasttissue while acting as an agonist of the ER in bone (Grese et al., Proc.Natl. Acad. Sci. USA 94, 14105-14110 (1997)). Because of the tissueselective effects seen for Tamoxifen, this agent and agents like it arereferred to as “partial-agonist” or partial-antagonist”. In addition tosynthetically derived non-endogenous ligands, non-endogenous ligands forNHR's can be obtained from food sources (Regal et al., Proc. Soc. Exp.Biol. Med. 223, 372-378 (2000) and Hempstock et al., J. Med. Food 2,267-269 (1999)). The falconoid phytoestrogens are an example of anunnatural ligand for SB-NHR's that are readily obtained from a foodsource such as soy (Quella et al., J. Clin. Oncol. 18, 1068-1074 (2000)and Banz et al., J. Med. Food 2, 271-273 (1999)). The ability tomodulate the transcriptional activity of individual NHR by the additionof a small molecule ligand, makes them ideal targets for the developmentof pharmaceutical agents for a variety of disease states.

As mentioned above, non-natural ligands can be synthetically engineeredto serve as modulators of the function of NHR's. In the case ofSB-NHR's, engineering of an unnatural ligand can include theidentification of a core structure which mimics the natural steroid coresystem. This can be achieved by random screening against severalSB-NHR's or through directed approaches using the available crystalstructures of a variety of NHR ligand binding domains (Bourguet et al.,Nature 375, 377-382 (1995), Brzozowski, et al., Nature 389, 753-758(1997), Shiau et al., Cell 95, 927-937 (1998) and Tanenbaum et al.,Proc. Natl. Acad. Sci. USA 95, 5998-6003 (1998)). Differentialsubstitution about such a steroid mimic core can provide agents withselectivity for one receptor versus another. In addition, suchmodifications can be employed to obtain agents with agonist orantagonist activity for a particular SB-NHR. Differential substitutionabout the steroid mimic core can result in the formation of a series ofhigh affinity agonists and antagonists with specificity for, forexample, ER versus PR versus AR versus GR versus MR. Such an approach ofdifferential substitution has been reported, for example, for quinolinebased modulators of steroid NHR in J. Med. Chem., 41, 623 (1999); WO9749709; U.S. Pat. No. 5,696,133; U.S. Pat. No. 5,696,130; U.S. Pat. No.5,696,127; U.S. Pat. No. 5,693,647; U.S. Pat. No. 5,693,646; U.S. Pat.No. 5,688,810; U.S. Pat. No. 5,688,808 and WO 9619458, all incorporatedherein by reference.

The compounds of the present invention comprise a core which serves as asteroid mimic, and are useful as modulators of the function of steroidbinding nuclear hormone receptors, as well as other NHR as describedfollowing.

SUMMARY OF THE INVENTION

The present invention provides fused cyclic compounds of the followingformula I and salts thereof, which compounds are especially useful asmodulators of nuclear hormone receptor function:

As used in formula I, and throughout the specification, the symbols havethe following meanings unless otherwise indicated, and are, for eachoccurrence, independently selected:

-   G is an aryl or heterocyclo (e.g., heteroaryl) group, where said    group is mono- or polycyclic, and which is optionally substituted at    one or more positions, preferably with hydrogen, alkyl or    substituted alkyl, alkenyl or substituted alkenyl, alkynyl or    substituted alkynyl, halo, cycloalkyl or substituted cycloalkyl,    cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl,    heterocyclo or substituted heterocyclo, arylalkyl or substituted    arylalkyl, heterocycloalkyl or substituted heterocycloalkyl, CN,    R¹OC—O, R¹C═O, R¹C═S, R¹HNC═O, R¹R²NC—O, HOCR³R³, nitro, R¹OCH₂,    R¹O, NH₂, NR⁴R⁵, SR¹, S═OR¹, SO₂R¹, SO₂OR¹, SO₂NR¹R^(1″),    (R¹O)(R^(1′)O)P═O, oxo, (R¹)(R^(1″))P═O, or (R^(1″))(NHR¹)P═O;-   Z₁ is O, S, NH, or NR⁶;-   Z₂ is O, S, NH, or NR⁶;-   A₁ is CR⁷ or N;-   A₂ is CR⁷ or N;-   Y is J—J′—J″ where J is (CR⁷R^(7′))n and n=0-3, J′ is a bond or O,    S, S═O, SO₂, NH, NR⁷, C═O, OC═O, NR¹C═O, CR⁷R^(7′), C═CR⁸R^(8′),    R²P═O, R²P═S, R²OP═O, R²NHP═O, OP═OOR², OP═ONHR², OP═OR², OSO₂,    C═NR⁷, NHNH, NHNR⁶, NR⁶NH, N═N, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo or aryl or substituted aryl, and J″ is    (CR⁷R^(7′))n and n=0-3, where Y is not a bond (i.e., if J′ is a    bond, then in at least one of J or J″ (each defined as    (CR⁷R^(7′))n), n is not zero);-   W is CR⁷R^(7′)—CR⁷R^(7′), CR⁸═CR^(8′), CR⁷R^(7′)—C═O, C═O—C═O,    CR⁷R^(7′)—C═CH₂, C═CH₂—C═CH₂, CR⁷R^(7′)—C═NR¹, C═NR¹—C═NR¹,    NR⁹—CR⁷R^(7′), N═CR⁸, N═N, NR⁹—NR^(9′), S—CR⁷R^(7′), SO—CR⁷R^(7′),    SO₂—CR⁷R^(7′), cycloalkyl or substituted cycloalkyl, cycloalkenyl or    substituted cycloalkenyl, heterocyclo or substituted heterocyclo, or    aryl or substituted aryl, wherein when W is not NR⁹—R⁷R^(7′), N═CR⁸,    N═N, NR⁹—NR^(9′), S—CR⁷R^(7′), SO—CR⁷R^(7′), SO₂—CR⁷R^(7′), or    heterocyclo or substituted heterocyclo, then J′ must be O, S, S═O,    SO₂, NH, NR⁷, OC═O, NR¹C═O, OP═OOR², OP═ONHR², OSO₂, NHNH, NHNR⁶,    NR⁶NH, or N═N; or-   when W is CR⁷R^(7′)—CR⁷R^(7′), the R⁷ and R⁷ substituents in each    occurrence may be taken together to form a substituted or    unsubstituted carbocyclic or substituted or unsubstituted    heterocyclic ring system which can be formed by any combination of    R⁷ and R^(7′) attached to the same carbon atom;-   Q₁ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl,    arylalkyl or substituted arylalkyl, alkynyl or substituted alkynyl,    aryl or substituted aryl, heterocyclo (e.g., heteroaryl) or    substituted heterocyclo (e.g., substituted heteroaryl), halo, CN,    R¹OC═O, R⁴C═O, R⁵R⁶NC═O, HOCR⁷R^(7′), nitro, R¹OCH₂, R¹O, NH₂,    C═OSR¹, SO₂R¹ or NR⁴R⁵;-   Q₂ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl,    arylalkyl or substituted arylalkyl, alkynyl or substituted alkynyl,    aryl or substituted aryl, heterocyclo (e.g., heteroaryl) or    substituted heterocyclo (e.g., substituted heteroaryl), halo, CN,    R¹OC═O, R⁴C═O, R⁵R⁶NC═O, HOCR⁷R^(7′), nitro, R¹OCH₂, R¹O, NH₂,    C═OSR¹, SO₂R¹ or NR⁴R⁵;-   L is a bond, (CR⁷R^(7′))n, NH, NR⁵, NH(CR⁷R^(7′))n, or    NR⁵(CR⁷R^(7′))n, where n=0-3;-   R¹ and R^(1′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl;-   R² is alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl;-   R³ and R^(3′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, halo, CN, hydroxylamine, hydroxamide, alkoxy or    substituted alkoxy, amino, NR¹R², thiol, alkylthio or substituted    alkylthio;-   R⁴ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, R¹C═O, R¹OC═O,    R¹NHC═O, SO₂OR¹, SO₂R¹ or SO₂NR¹R^(1′);-   R⁵ is alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, R¹C═O,    R¹NHC═O, SO₂R¹, SO₂OR¹, or SO₂NR¹R^(1′);-   R⁶ is alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, CN, OH, OR¹,    R¹C═O, R¹NHC═O, SO₂R¹, SO₂OR¹, or SO₂NR¹R^(1′);-   R⁷ and R^(7′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, halo, CN, OR⁴,    nitro, hydroxylamine, hydroxylamide, amino, NHR⁴, NR²R⁵, NR⁵R⁵,    NOR¹, thiol, alkylthio or substituted alkylthio, HOC═O, R¹C═O,    R¹(C═O)O, R¹OC═O, R¹NHC═O, NH₂C═O, SO₂R¹, SOR¹, PO₃R¹R^(1′),    R¹R^(1′)NC═O, C═OSR¹, SO₂R¹, SO₂OR¹, or SO₂NR¹R^(1′), or, wherein A₁    or A₂ contains a group R⁷ and W contains a group R⁷, said R⁷ groups    of A₁ or A₂ and W together form a heterocyclic ring;-   R⁸ and R^(8′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, nitro, halo, CN, OR¹, amino, NHR⁴, NR²R⁵, NOR¹, alkylthio    or substituted alkylthio, C═OSR¹, R¹OC═O, R¹C═O, R¹NHC═O,    R¹R^(1′)NC═O, SO₂OR¹, S═OR¹, SO₂R¹, PO₃R¹R^(1′), or SO₂NR¹R^(1′);    and-   R⁹ and R^(9′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, CN, OH, OR¹, R¹C═O, R¹OC═O, R¹NHC═O, SO₂R¹, SO₂OR¹, or    SO₂NR¹R^(1′).

Compounds within formula I are novel, a preferred subgenus of which isthe following formula Ia:

where G, L, Z₁, Z₂, A₁, A₂, Q₁ and Q₂ are as defined above;

-   Y′ is J—J′—J″ where J is (CR⁷R^(7′))n and n=0-3, J′ is a bond or O,    S, S═O, SO₂, NH, NR⁷, CR⁷R^(7′), R²P═O, R²P═S, R²OP═O, R²NHP═O,    OP═OOR², OP═ONHR², OSO₂, NHNH, NHNR⁶, NR⁶NH, N═N, cycloalkyl or    substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or    heterocyclo or substituted heterocyclo, and J″ is (CR⁷R^(7′))n and    n=0-3, where Y is not a bond; and-   W′ is CR⁷R^(7′)—CR⁷R^(7′), CR⁷R^(7′)—C═O, C═O—C═O, CR⁷R^(7′)—C═CH₂,    C═CH₂—C═CH₂, CR⁷R^(7′)—C═NR¹, C═NR¹—C═NR¹, NR⁹—CR⁷R^(7′), N═CR⁸,    N═N, NR⁹—NR^(9′), cycloalkyl or substituted cycloalkyl, cycloalkenyl    or substituted cycloalkenyl, heterocyclo or substituted heterocyclo,    or aryl or substituted aryl, wherein when W′ is not NR⁹—CR⁷R^(7′),    N═CR¹, N═N, NR⁹—NR^(9′), or heterocyclo or substituted heterocyclo,    then J′ must be O, S, S═O, SO₂, NH, NR⁷, OP═OOR², OP═ONHR², OSO₂,    NHNH, NHNR⁶, NR⁶NH, or N═N; or-   when W′ is CR⁷R^(7′)—CR⁷R^(7′), the R⁷ and R⁷ substituents in each    occurrence may be taken together to form a substituted or    unsubstituted carbocyclic or substituted or unsubstituted    heterocyclic ring system which can be formed by any combination of    R⁷ and R^(7′) attached to the same carbon atom; or alternatively,-   Y′ is NR⁷—CR⁷R^(7′) and W′ is CR⁸═CR⁸; or, alternatively,-   Y′ is CR⁷R^(7′)—C═O and W′ is NR⁹—CR⁷R^(7′);-   where R², R⁶, R⁷, R^(7′), R⁸, R⁹ and R^(9′) are as defined above and    with the provisos that    -   (1) when Y′ is —O—, Q₁ and Q₂ are hydrogen, Z₁ and Z₂ are O, W′        is —CH₂—CH₂—, and A₁ and A₂ are CH, then G—L is not phenyl,        monosubstituted phenyl or phenyl which is substituted with two        or more of the following groups: methoxy, halo, NO₂, methyl,        CH₃—S—, OH, CO₂H, trifluoromethyl, —C(O)—C₆H₅, NH₂, 4-7-epoxy,        hexahydro-1H-isoindole-1,3(2H)dione, or —C(O)—CH₃;    -   (2) when Y′ is —O—, Q₁ and Q₂ are hydrogen, Z₁ and Z₂ are O, W′        is CH₂—CH₂, and one of A₁ and A₂ is CH and the other is CR⁷,        then G—L is not unsubstituted phenyl;    -   (3) when Y′ is —O—, Q₁ and Q₂ are hydrogen, Z₁ and Z₂ are O, W′        is CH₂—CH₂, and one of A₁ and A₂ is CH and the other is C—CH₃,        then G—L is not phenyl substituted with chloro and/or methyl;    -   (4) when Y′ is —O— or —S—, Q₁ and Q₂ are hydrogen, Z₁ and Z₂ are        O, W′ is CH₂—CH₂, and one of A₁ and A₂ is CH and the other is CH        or C-alkyl, then G—L is not N-substituted piperazine-alkyl- or        N-substituted imidazolidine-alkyl-;    -   (5) when Y′ is —O—; Q₁ and Q₂ are hydrogen, Z₁ and Z₂ are O, W′        is CH₂—CH₂, and A₁ and A₂ are CH, then G—L is not oxazole or        triazole;    -   (6) when Y′ is —O—; Q₁ and Q₂ are hydrogen or methyl, Z₁ and Z₂        are O, W′ is CH₂—CH₂, and A₁ and A₂ are CH or C—CH₃, then G—L is        not thiazole or substituted thiazole (in addition such compounds        where G—L is optionally substituted thiadiazole or partially        saturated thiazole are optionally removed by proviso where A₁        and A₂ are both CH);    -   (7) when Y′ contains a group J′ selected from S, S═O, SO₂, NH,        NR⁷, R²P═O, R²P═S, R²OP═O, R²NHP═O, OP═OOR², OP═ONHR², OSO₂,        NHNH, NHR⁶, NR⁶NH or N═N, W′ is CR⁷R^(7′)—CR⁷R^(7′), and Z₁ and        Z₂ are 0, then G—L is not unsubstituted phenyl;    -   (8) when Y′ is NR⁷, W′ is unsubstituted or substituted phenyl,        and Q₁ and Q₂ are hydrogen, then Z₁ and Z₂ are not O;    -   (9) when Y′ is —O—, Q₁ and Q₂ are hydrogen, Z₁ and Z₂ are O, W′        is dihydroisoxazole bearing an optionally substituted phenyl        group, and A₁ and A₂ are CH, then G—L is not unsubstituted        phenyl or dichlorophenyl;    -   (10) when Y′ is O, Q₁ and Q₂ are hydrogen, Z₁ and Z₂ are O, W′        is ethylene oxide, and A₁ and A₂ are CH, then G—L is not        methylphenyl or chlorophenyl;    -   (11) when Y′ is NR⁷—CR⁷R^(7′), W′ is CR⁸═CR^(8′), Q₁ and Q₂ are        hydrogen, A₁ and A₂ are CH, C—CH₃, C—CH₂—C₆H₅ or C—CH₂—CH₃, and        Z₁ and Z₂ are O, then G—L is not unsubstituted phenyl,        monosubstituted phenyl or methylpyridinyl;    -   (12) when Y′ is CR⁷R^(7′)—C═O, W′ is NR⁹—CR⁷R^(7′), Q₁ and Q₂        are hydrogen, A₁ and A₂ are CH, and Z₁ and Z₂ are O, then G—L is        not unsubstituted phenyl;    -   (13) when Y′ is CHR^(7′)—NR⁷ where R^(7′) is unsubstituted        phenyl, methoxy or ethoxy and R⁷ is unsubstituted phenyl, methyl        or —C(O)—C₆H₅, W′ is dimethoxyphenylene or unsubstituted        phenylene, Z₁ and Z₂ are O, Q₁ and Q₂ are hydrogen, and A₁ and        A₂ are CH, C—CN, C—C(O)—C₆H₅, or —C(O)— dimethoxyphenyl, then        G—L is not unsubstituted phenyl;    -   (14) the compound of formula Ia is not        6,10-epithio-4H-thieno-[3′,4′:5,6]cyclooct[1,2-f]isoindole-7,9(5H,8H)-dione,        8-(3,5-dichlorophenyl)-6,6a,9a,        10,11,12,-hexahydro-1,3,6,10-tetramethyl-2,2,13-trioxide,        (6R,6aR,9aS,10S);    -   (15) when Y′ is O, W′ is —CH₂—CH₂—, Q₁ and Q₂ are methyl, Z₁ and        Z₂ are O, and A₁ and A₂ are CH, then G—L is not unsubstituted        phenyl, phenyl substituted with methoxy, phenyl-alkyl-, or        morpholine-alkyl, nor is the compound bridged to itself through        a group L which is alkylene to form a bis compound;    -   (16) when Y′ is —O—, Q₁ and Q₂ are hydrogen, Z₁ and Z₂ are O, W′        is CR⁷R^(7′)—CR⁷R^(7′), and A₁ and A₂ are CH, then G—L is not an        unsubstituted phenyl group; and    -   (17) when Y′ is —O—, Q₁ and Q₂ are hydrogen, Z₁ and Z₂ are O, W′        is cyclopentyl, cyclohexyl, 3-phenyl-2-isoxazoline or        CR⁷R^(7′)—CR⁷R^(7′) where R⁷ and R^(7′) are each independently        defined as Cl, Br, H and 4-butyrolactone and R⁷ and R^(7′) are        not all simultaneously H, and A₁ and A₂ are CH, then G—L is not        an unsubstituted naphthyl ring or a monosubstituted phenyl ring,        where said substituent is methoxy, Br, Cl, NO₂, methyl, ethyl,        CH₂-phenyl, S-phenyl, or O-phenyl.

Preferably, compounds of formula I are monomeric, and are not comprisedwithin other oligomers or polymers.

Another preferred novel subgenus is that of the following formula Ib:

where G, Z₁, Z₂, Q₁ and Q₂ are as defined above;

-   Y′ is J—J′—J″ where J is (CR⁷R^(7′))n and n=0-3, J′ is a bond or O,    S, S═O, SO₂, NH, NR⁷, CR⁷R^(7′), R²P═O, R²P═S, R²OP═O, R²NHP═O,    OP═OOR², OP═ONHR², OSO₂, NHNH, NHNR⁶, NR⁶NH, N═N, cycloalkyl or    substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or    heterocyclo or substituted heterocyclo, and J″ is (CR⁷R^(7′))n and    n=0-3, where Y is not a bond; and-   W′ is CR⁷R^(7′)—R⁷R^(7′), CR⁷R^(7′)—C═O, C═O—C═O, CR⁷R^(7′)—C═CH₂,    C═CH₂—C═CH₂, CR⁷R^(7′)—C═NR¹, C═NR¹—C═NR¹, NR⁹—CR⁷R^(7′), N═CR⁸,    N═N, NR⁹—NR^(9′), cycloalkyl or substituted cycloalkyl, cycloalkenyl    or substituted cycloalkenyl, heterocyclo or substituted heterocyclo,    or aryl or substituted aryl, wherein when W′ is not NR⁹—CR⁷R^(7′),    N═CR⁸, N═N, NR⁹—NR^(9′), or heterocyclo or substituted heterocyclo,    then J′ must be O, S, S═O, SO₂, NH, NR⁷, OP═OOR², OP═ONHR², OSO₂,    NHNH, NHNR⁶, NR⁶NH, or N═N; or-   when W′ is CR⁷R^(7′)—CR⁷R^(7′), the R⁷ and R^(7′) substituents in    each occurrence may be taken together to form a substituted or    unsubstituted carbocyclic or substituted or unsubstituted    heterocyclic ring system which can be formed by any combination of    R⁷ and R^(7′) attached to the same carbon atom; or alternatively,-   Y′ is CR⁷R^(7′)—C═O and W′ is NR⁹— CR⁷R^(7′);-   L is a bond; and    A₁ and A₂ are as defined above, especially where A₁ and/or A₂ are    alkyl or optionally substituted alkyl (preferred such optional    substituents being one or more groups V¹ defined below), with the    proviso that, when Y′=O and W′=—CH₂—CH₂—, then at least one of A₁ or    A₂ is not CH;    with the further provisos (2), (3), (6), (7) and (8) above.

The compounds of formula I and salts thereof comprise a core which canserve as a steroid mimic (and do not require the presence of asteroid-type (e.g., cyclopentanoperhydrophenanthrene analog) structure).

FURTHER DESCRIPTION OF THE INVENTION

The following are definitions of terms used in the presentspecification. The initial definition provided for a group or termherein applies to that group or term throughout the presentspecification individually or as part of another group, unless otherwiseindicated.

The terms “alkyl” and “alk” refers to a straight or branched chainalkane (hydrocarbon) radical containing from 1 to 12 carbon atoms,preferably 1 to 6 carbon atoms. Exemplary such groups include, but arenot limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.“Substituted alkyl” refers to an alkyl group substituted with one ormore substituents, preferably 1 to 4 substituents, at any availablepoint of attachment. Exemplary substituents include but are not limitedto one or more of the following groups: halo (e.g., a single halosubstituent or multiple halo substitutents forming, in the latter case,groups such as a perfluoroalkyl group or an alkyl group bearing Cl₃ orCF₃), alkoxy, alkylthio, hydroxy, carboxy (i.e., —COOH), alkoxycarbonyl,alkylcarbonyloxy, amino (i.e., —NH₂), carbamoyl or substitutedcarbamoyl, carbamate or substituted carbamate, urea or substituted urea,amidinyl or substituted amidinyl, thiol (i.e., —SH), aryl, heterocycle,cycloalkyl, heterocycloalkyl, —S-aryl, —S-heterocycle, —S═O-aryl,—S═O-heterocycle, arylalkyl-O—, —S(O)₂-aryl, —S(O)₂-heterocycle,—NHS(O)₂-aryl, —NHS(O)₂-heterocycle, —NHS(O)₂NH-aryl,—NHS(O)₂NH-heterocycle, —P(O)₂-aryl, —P(O)₂-heterocycle, —NHP(O)₂-aryl,—NHP(O)₂-heterocycle, —NHP(O)₂NH-aryl, —NHP(O)₂NH-heterocycle, —O-aryl,—O-heterocycle, —NH-aryl, —NH-heterocycle, —NHC═O-aryl, —NHC═O-alkyl,—NHC═O-heterocycle, —OC═O-aryl, —OC═O-heterocycle, —NHC═ONH-aryl,—NHC═ONH-heterocycle, —OC═OO-aryl, —OC═OO-heterocycle, —OC═ONH-aryl,—OC═ONH-heterocycle, —NHC═OO-aryl, —NHC═OO-heterocycle, —NHC═OO-alkyl,—C═ONH-aryl, —C═ONH-heterocycle, —C═OO-aryl, —C═OO-heterocycle,—N(alkyl)S(O)₂-aryl, —N(alkyl)S(O)₂-heterocycle, —N(alkyl)S(O)₂NH-aryl,—N(alkyl)S(O)₂NH-heterocycle, —N(alkyl)P(O)₂-aryl,—N(alkyl)P(O)₂-heterocycle, —N(alkyl)P(O)₂NH-aryl,—N(alkyl)P(O)₂NH-heterocycle, —N(alkyl)-aryl, —N(alkyl)-heterocycle,—N(alkyl)C═O-aryl, —N(alkyl)C═O-heterocycle, —N(alkyl)C—ONH-aryl,—N(alkyl)C═ONH-heterocycle, —OC═ON(alkyl)-aryl,—OC═ON(alkyl)-heterocycle, —N(alkyl)C═OO-aryl,—N(alkyl)C═OO-heterocycle, —C═ON(alkyl)-aryl, —C═ON(alkyl)-heterocycle,—NHS(O)₂N(alkyl)-aryl, —NHS(O)₂N(alkyl)-heterocycle,—NHP(O)₂N(alkyl)-aryl, NHP(O)₂N(alkyl)-heterocycle, —NHC═ON(alkyl)-aryl,—NHC═ON(alkyl)-heterocycle, —N(alkyl)S(O)₂N(alkyl)-aryl,—N(alkyl)S(O)₂N(alkyl)-heterocycle, —N(alkyl)P(O)₂N(alkyl)-aryl,—N(alkyl)P(O)₂N(alkyl)-heterocycle, —N(alkyl)C═ON(alkyl)-aryl, and—N(alkyl)C═ON(alkyl)-heterocycle. In the aforementioned exemplarysubstitutents, in each instance, groups such as “alkyl”, “aryl” and“heterocycle” can themselves be optionally substituted; for example,“alkyl” in the group “NCH═OO-alkyl” recited above can be optionallysubstituted so that both “NHC═OO-alkyl” and “NHC═OO-substituted alkyl”are exemplary substitutents. Exemplary alkyl substituents also includegroups such as “T” and “T-R¹²” (which are defined below), especially forsubstituted alkyl groups within A₁ or A₂.

The term “alkenyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-carbon double bond. Exemplary such groups include ethenyl orallyl. “Substituted alkenyl” refers to an alkenyl group substituted withone or more substituents, preferably 1 to 4 substituents, at anyavailable point of attachment. Exemplary substituents include, but arenot limited to, alkyl or substituted alkyl, as well as those groupsrecited above as exemplary alkyl substituents.

The term “alkynyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least one carbon tocarbon triple bond. Exemplary such groups include ethynyl. “Substitutedalkynyl” refers to an alkynyl group substituted with one or moresubstituents, preferably 1 to 4 substituents, at any available point ofattachment. Exemplary substituents include, but are not limited to,alkyl or substituted alkyl, as well as those groups recited above asexemplary alkyl substituents.

The term “cycloalkyl” refers to a fully saturated cyclic hydrocarbongroup containing from 1 to 4 rings and 3 to 8 carbons per ring.Exemplary such groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc. “Substituted cycloalkyl” refers to a cycloalkyl groupsubstituted with one or more substituents, preferably 1 to 4substituents, at any available point of attachment. Exemplarysubstituents include, but are not limited to, nitro, cyano, alkyl orsubstituted alkyl, as well as those groups recited above as exemplaryalkyl substituents, and as previously mentioned as preferred arylsubstituents in the definition for G. Exemplary substituents alsoinclude spiro-attached or fused cyclic substituents, especiallycycloalkenyl or substituted cycloalkenyl.

The term “cycloalkenyl” refers to a partially unsaturated cyclichydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring.Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl,etc. “Substituted cycloalkenyl” refers to a cycloalkenyl groupsubstituted with one more substituents, preferably 1 to 4 substituents,at any available point of attachment. Exemplary substituents include butare not limited to nitro, cyano, alkyl or substituted alkyl, as well asthose groups recited above as exemplary alkyl substituents, and aspreviously mentioned as preferred aryl substituents in the definitionfor G. Exemplary substituents also include spiro-attached or fusedcyclic substituents, especially cycloalkyl or substituted cycloalkyl.

The terms “alkoxy” or “alkylthio” refer to an alkyl group as describedabove bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—),respectively. The terms “substituted alkoxy” or “substituted alkylthio”refer to a substituted alkyl group as described above bonded through anoxygen or sulfur linkage, respectively.

The term “alkoxycarbonyl” refers to an alkoxy group bonded through acarbonyl group.

The term “alkylcarbonyl” refers to an alkyl group bonded through acarbonyl group. The term “alkylcarbonyloxy” refers to an alkylcarbonylgroup bonded through an oxygen linkage.

The terms “arylalkyl”, “substituted arylalkyl,” “cycloalkylalkyl,”“substituted cycloalkylalkyl,” “cycloalkenylalkyl”, “substitutedcycloalkenylalkyl”, “heterocycloalkyl” and “substitutedheterocycloalkyl” refer to aryl, cycloalkyl, cycloalkenyl andheterocyclo groups bonded through an alkyl group, substituted on thearyl, cycloalkyl, cycloalkenyl or heterocyclo and/or the alkyl groupwhere indicated as “substituted.”

The term “aryl” refers to cyclic, aromatic hydrocarbon groups which have1 to 5 aromatic rings, especially monocyclic or bicyclic groups such asphenyl, biphenyl or naphthyl. Where containing two or more aromaticrings (bicyclic, etc.), the aromatic rings of the aryl group may bejoined at a single point (e.g., biphenyl), or fused (e.g., naphthyl,phenanthrenyl and the like). “Substituted aryl” refers to an aryl groupsubstituted by one or more substituents, preferably 1, 2, 3, 4 or 5substituents, at any point of attachment. Exemplary substituentsinclude, but are not limited to, nitro, cycloalkyl or substitutedcycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano,alkyl-S(O)_(m)— (m=0, 1 or 2), alkyl or substituted alkyl, as well asthose groups recited above as exemplary alkyl substituents and aspreviously mentioned as preferred aryl substituents in the definitionfor G. Exemplary substituents also include fused cyclic substituents,such as heterocyclo or cycloalkenyl, or substituted heterocyclo orcycloalkenyl, groups (e.g., thereby forming a fluoroenyl,tetrahydronapthalenyl, or dihydroindenyl group).

“Carbamoyl” refers to the group —CONH— which is bonded on one end to theremainder of the molecule and on the other to hydrogen or an organicmoiety (such as alkyl, substituted alkyl, aryl, substituted aryl,heterocycle, alkylcarbonyl, hydroxyl and substituted nitrogen).“Carbamate” refers to the group —O—CO—NH— which is bonded on one end tothe remainder of the molecule and on the other to hydrogen or an organicmoiety (such as those listed above). “Urea” refers to the group—NH—CO—NH— which is bonded on one end to the remainder of the moleculeand on the other to hydrogen or an organic moiety (such as those listedabove). “Amidinyl” refers to the group —C(═NH)(NH₂). “Substitutedcarbamoyl,” “substituted carbamate,” “substituted urea” and “substitutedamidinyl” refer to carbamoyl, carbamate, urea or amidinyl groups asdescribed above in which one more of the hydrogen groups are replaced byan organic moiety (such as those listed above).

The terms “heterocycle”, heterocyclic” and “heterocyclo” refer to fullysaturated, or partially or fully unsaturated, including aromatic (i.e.,“heteroaryl”) cyclic groups (for example, 3 to 7 membered monocyclic, 7to 11 membered bicyclic, or 10 to 16 membered tricyclic ring systems)which have at least one heteroatom in at least one carbonatom-containing ring. Each ring of the heterocyclic group containing aheteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogenatoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfurheteroatoms may optionally be oxidized and the nitrogen heteroatoms mayoptionally be quaternized. (The term “heteroarylium” refers to aheteroaryl group bearing a quaternary nitrogen atom and thus a positivecharge.) The heterocyclic group may be attached to the remainder of themolecule at any heteroatom or carbon atom of the ring or ring system. Itis understood that, where W or W′ are cycloalkyl or substitutedcycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo orsubstituted heterocyclo, or aryl or substituted aryl, that A1 and A2 canbe separately bonded to different (such as adjacent) ring atoms on saidgroups. Exemplary monocyclic heterocyclic groups include ethylene oxide,azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl,hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl,morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinylsulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like.Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl,benzothiazolyl, benzodioxolyl, benzoxazolyl, benzoxadiazolyl,benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl,benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydrobenzodioxinyl, dihydrodioxidobenzothiophenyl, dihydroisoindolyl,dihydroindolyl, dihydroquinolinyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyland the like. Exemplary tricyclic heterocyclic groups includecarbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl,phenanthridinyl, xanthenyl and the like.

“Substituted heterocycle,” “substituted heterocyclic,” and “substitutedheterocyclo” (such as “substituted heteroaryl”) refer to heterocycle,heterocyclic or heterocyclo groups substituted with one or moresubstituents, preferably 1 to 4 substituents, at any available point ofattachment. Exemplary substituents include, but are not limited to,cycloalkyl or substituted cycloalkyl, cycloalkenyl or substitutedcycloalkenyl, nitro, oxo (i.e., ═O), cyano, alkyl-S(O)_(m)— (m=0, 1 or2), alkyl or substituted alkyl, as well as those groups recited above asexemplary alkyl substituents, and as previously mentioned as preferredheterocyclo substituents in the definition for G.

The term “quaternary nitrogen” refers to a tetravalent positivelycharged nitrogen atom including, for example, the positively chargednitrogen in a tetraalkylammonium group (e.g., tetramethylammonium,N-methylpyridinium), the positively charged nitrogen in protonatedammonium species (e.g., trimethylhydroammonium, N-hydropyridinium), thepositively charged nitrogen in amine N-oxides (e.g.,N-methyl-morpholine-N-oxide, pyridine-N-oxide), and the positivelycharged nitrogen in an N-amino-ammonium group (e.g., N-aminopyridinium).

The terms “halogen” or “halo” refer to chlorine, bromine, fluorine oriodine.

The terms “hydroxylamine” and “hydroxylamide” refer to the groups OH—NH—and OH—NH—CO—, respectively.

When a functional group is termed “protected”, this means that the groupis in modified form to mitigate, especially preclude, undesired sidereactions at the protected site. Suitable protecting groups for themethods and compounds described herein include, without limitation,those described in standard textbooks, such as Greene, T. W. et al.,Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).

When a term such as “(CRR)n” is used, it denotes an optionallysubstituted alkyl chain existing between the two fragments to which itis bonded, the length of which chain is defined by the range describedfor the term n. An example of this is n=0-3, implying from zero to three(CRR) units existing between the two fragments, which are attached tothe primary and terminal (CRR) units. In the situation where the term nis set to zero (n=0) then a bond exists between the two fragmentsattached to (CRR).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

Divalent groups, such as those in the definition of W (e.g.,NR⁹—CR⁷R^(7′)), may be bonded in either direction to the remainder ofthe molecule (e.g.,

for the aforementioned group within the definition of W).

Carboxylate anion refers to a negatively charged group —COO⁻.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of the formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains both a basic moiety,such as but not limited to a pyridine or imidazole, and an acidic moietysuch as but not limited to a carboxylic acid, zwitterions (“innersalts”) may be formed and are included within the term “salt(s)” as usedherein. Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful,e.g., in isolation or purification steps which may be employed duringpreparation. Salts of the compounds of the formula I may be formed, forexample, by reacting a compound I with an amount of acid or base, suchas an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

The compounds of formula I which contain a basic moiety, such as but notlimited to an amine or a pyridine or imidazole ring, may form salts witha variety of organic and inorganic acids. Exemplary acid addition saltsinclude acetates (such as those formed with acetic acid or trihaloaceticacid, for example, trifluoroacetic acid), adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates),lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g.,2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates,persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of formula I which contain an acidic moiety, such but notlimited to a carboxylic acid, may form salts with a variety of organicand inorganic bases. Exemplary basic salts include ammonium salts,alkali metal salts such as sodium, lithium and potassium salts, alkalineearth metal salts such as calcium and magnesium salts, salts withorganic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glycamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl halides (e.g. methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug” as employed herein denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, or a salt and/or solvate thereof. Solvates of the compoundsof formula I include, for example, hydrates.

Compounds of the formula I, and salts thereof, may exist in theirtautomeric form (for example, as an amide or imino ether). All suchtautomeric forms are contemplated herein as part of the presentinvention.

All stereoisomers of the present compounds (for example, those which mayexist due to asymmetric carbons on various substituents), includingenantiomeric forms and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers(e.g., as a pure or substantially pure optical isomer having a specifiedactivity), or may be admixed, for example, as racemates or with allother, or other selected, stereoisomers. The chiral centers of thepresent invention may have the S or R configuration as defined by theIUPAC 1974 Recommendations. The racemic forms can be resolved byphysical methods, such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates by any suitable method,including without limitation, conventional methods, such as, forexample, salt formation with an optically active acid followed bycrystallization.

All configurational isomers of the compounds of the present inventionare contemplated, either in admixture or in pure or substantially pureform. The definition of compounds of the present invention embraces bothcis (Z) and trans (E) alkene isomers, as well as cis and trans isomersof cyclic hydrocarbon or heterocyclo rings. In certain cases, forexample, the exo or endo conformation can be preferred for the fusedring system bonded to G—L in formula I. For example, for androgenreceptor antagonists (or selective androgen receptor modulators), whereY is O or NR⁷, the exo configuration can be preferred, while for mostother definitions of Y, the endo configuration can be preferred. As canbe appreciated, the preferred configuration can be a function of theparticular compound and its preferred activity. Separation ofconfigurational isomers can be achieved by any suitable method, such ascolumn chromatography.

Throughout the specifications, groups and substituents thereof may bechosen to provide stable moieties and compounds.

Embodiments indicated herein as exemplary or preferred are intended tobe illustrative and not limiting.

Methods of Preparation

The compounds of the present invention may be prepared by methods suchas those illustrated in the following Schemes I to XI. Solvents,temperatures, pressures, and other reaction conditions may readily beselected by one of ordinary skill in the art. Starting materials arecommercially available or readily prepared by one of ordinary skill inthe art. Combinatorial techniques may be employed in the preparation ofcompounds, for example, where the intermediates possess groups suitablefor these techniques. See the following which describe other methodswhich may be employed in the preparation of compounds of the presentinvention: Li, et al., Eur. J. Org. Chem. 9, 1841-1850 (1998); Li, Y-Q,Synlett. 5, 461-464 (1996); Thiemann, et al., Bull. Chem. Soc. Jpn. 67,1886-1893 (1994); Tsuge et al., Heterocycles 14, 423-428 (1980); Ward etal., Can J. Chem. 75, 681-693 (1997); Ward et al., Can J. Chem. 69,1487-1497 (1991); Ward et al., Tetrahedron Lett. 31, 845-848 (1990);Fleming et al., J. Org. Chem. 44, 2280-2282 (1979); Jankowski et al., J.Organomet. Chem. 595, 109-113 (2000); Keglevich et al., J. Organomet.Chem. 579, 182-189 (1999); Keglevich et al., J. Organomet. Chem. 570,49-539 (1998); Jankowski et al., Hetroat. Chem. 7, 369-374 (1996);Jankowski et al., J. Am. Chem. Soc. 113, 7011-7017 (1991); Quin et al.,Tetrahedron Lett. 31, 6473-6476 (1990); Quin et al., J. Org. Chem. 59,120-129 (1994); Quin et al., J. Org. Chem. 58, 6212-6216 (1993); Quin etal., Phosphorous, Sulfur Silicon Relat. Elem. 63, 349-362 (1991); Quinet al., Hetroat. Chem. 2, 359-367 (1991); Hussong et al., PhosphorusSulfur. 25, 201-212 (1985); Quin et al., J. Org. Chem. 51, 3341-3347(1986); Myers et al., J. Am. Chem. Soc. 114, 5684-5692 (1992); Myers etal., J. Am. Chem. Soc. 113, 6682-6683 (1991); Shen et al., U.S. Pat. No.5,817,679; Cordone et al., J. Am. Chem. Soc. 111, 5969-5970 (1989); Junget al., J. Chem. Soc. Commun. 630-632 (1984); Lay et al., J. Am. Chem.Soc. 104, 7658-7659 (1982); Gonzalez et al., J. Am. Chem. Soc. 117,3405-3421 (1995); Kreher et al., Chem. Ber. 125, 183-189 (1992); Simiget al., Synlett. 7, 425-426 (1990); Sha et al., J. Org. Chem. 55,2446-2450 (1990); Drew et al., J. Chem. Soc., Perkin Trans. 17,1277-1284 (1985); Kreher et al., Anorg. Chem., Org. Chem. 31B, 599-604(1976); Avalos et al., Tetrahedron Lett. 39, 9301-9304 (1998); Gousse etal., Macromolecules 31, 314-321 (1998); Mikhailyuchenko et al., Khim.Geterotsikl. Soedin. 6, 751-758 (1993); Lubowitz et al., U.S. Pat. No.4,476,184; Padwa et al., J. Org. Chem. 61, 3706-3714 (1996);Schlessinger et al., J. Org. Chem. 59, 3246-3247 (1994); Buchrneiser etal., WO Publication No. 9827423; Tanabe et al., Japanese Patent DocumentJP 07144477; Mochizucki et al., Japanese Patent Document JP 63170383;Hosoda et al., Japanese Patent Document JP 62053963; Onaka et al.,Japanese Patent Document JP 62053964; Kato et al., Japanese PatentDocument JP 53086035; Kato et al., Japanese Patent Document JP 51088631;Tottori et al., Japanese Patent Document JP 49124225; Augustin et al.,German Patent Document DD101271; Title et al., French Patent Document FR2031538; Gousse et al., Polym. Int. 48, 723-731 (1999); Padwa et al., J.Org. Chem. 62, 4088-4096 (1997); Theurillat-Moritz et al., Tetrahedron:Asymmetry 7, 3163-3168 (1996); Mathews et al., J. Carbohydr. Chem. 14,287-97 (1995); Srivastava et al., Natl. Acad. Sci. Lett. (India) 15,41-44 (1992); Mayorga et al., Rev. Cubana Quim. 4, 1-6 (1988); Kondoliet al., J. Chem. Res., Synop. 3, 76 (1987); Primelles et al., Cent.Azucar 7-14 (1985); Solov'eva et al., Khim. Geterotsikl. Soedin. 5,613-15 (1984); Liu et al., Yaoxue Xuebao 18, 752-759 (1983); Joshi etal., Indian J. Chem, Sect. B. 22B, 131-135 (1983); Amos et al., WOPublication No. 9829495; Odagiri et al., U.S. Pat. No. 4,670,536;Gallucci et al., European Patent Document EP 355435; Redmore, D. U.S.Pat. No. 3,821,232; Nakano et al., Heterocycles 35, 37-40 (1993);Tomisawa et al., Chem. Pharm. Bull. 36, 1692-1697 (1988); Krow et al.,J. HeterocycL Chem. 22, 131-135 (1985); Krow et al., J. Org. Chem. 47,1989-1993 (1982); Liu et al., Yaoxue Xuebao 18, 752-759 (1983);Nishikawa et al., Yaoxue Xuebao JP 01061457; and/or Rice et al., J. Med.Chem. 11, 183-185 (1968).

All documents cited in the present specification, such as those cited inthis “Methods of Preparation” as well as other sections herein, areincorporated herein by reference in their entirety. Reference to anydocument herein is not to be construed as an admission that suchdocument is prior art.

As illustrated in Scheme I, a diene of formula II can be reacted with adienophile of formula III, under conditions readily selected by oneskilled in the art (such as by the addition of heat (“Δ”)), to obtain acompound of formula IV, which is a compound of formula I. Anintermediate diene of formula II can be obtained from commercial sourcesor readily made by one skilled in the art, for example, in accordancewith the following literature documents and the references foundtherein: Hofman et al., J. Agric. Food Chem. 45, 898-906 (1997);Baciocchi et al., J. Chem. Soc., Perkin Trans. 2 8, 821-824 (1975); Wuet al., J. Heterocycles 38, 1507-1518 (1994); Yin et al., TetrahedronLett. 38, 5953-5954 (1997); Mic'ovic' et al., Tetrahedron 20, 2279-2287(1964); Gorbunova et al., J. Org. Chem. 35, 1557-1566 (1999); Rassu etal., Chem. Soc. Rev. 29, 109-118 (2000); Kaberdin et al., Russ. Chem.Rev. 68, 765-779 (1999); Barluenga et al., Aldrichimica Acta 32, 4-15(1999); Bogdanowicz-Szwed et al., Pol. Wiad. Chem. 52, 821-842 (1998);Casiraghi et al., Adv. Asymmetric Synth. 3, 113-189 (1998); and/orBaeckvall et al., Chem. Rev. 98, 2291-2312 (1998). An intermediatedieneophile of formula III can be obtained from commercial sources orreadily made by one skilled in the art, for example, in accordance withthe following literature references and the references found therein:Deshpande et al., Heterocycles 51, 2159-2162 (1999); Seijas et al., J.Chem. Res., Synop. 7, 420-421 (1999); Langer et al., Eur. J. Org. Chem.7, 1467-1470 (1998); Kita et al., Japanese Patent Document JP 09194458;Lopez-Alvarado et al., J. Org. Chem. 61, 5865-5870 (1996); Condon etal., U.S. Pat. No. 5,523,277; Sasakihara et al., Japanese PatentDocument JP 04290868; Igarashi et al., Japanese Patent Document JP04149173; Aoyama et al., Japanese Patent Document JP 04134063; Aoyama etal., Japanese Patent Document JP 04134062; Pastor et al., J. Org. Chem.53, 5776-5779 (1988); and/or Takahashi et al., Chem. Lett. 6, 1229-1232(1987).

As illustrated in Scheme II, compounds of formula I can be obtained byreaction of a primary amine of formula V with a substitutedanhydride-like intermediate of formula VI, for example, in a solventsuch as acetic acid with or without heating, to yield a compound offormula IV, which is a compound of formula I. Primary amines of formulaV can be obtained from commercial sources or readily synthesized by oneskilled in the art. Anhydride-like agents of formula VI can be obtainedfrom commercial sources or readily synthesized by one skilled in theart. The documents listed following describe exemplary approaches forthe synthesis of intermediates of formula VI as well as syntheticapproaches which can be applied to the synthesis of compounds of formulaIV (all incorporated herein by reference in their entirety): Kohler, E.P.; Tishler, M.; Potter, H.; Thompson, H. T. J. Am. Chem. Soc. 1939,1057-1061; Yur×ev, Y. K.; Zefirov, N. S. J. Gen. Chem. U.S.S.R. (Engl.Transl.) 1961, 31, 772-5; Norman G. Gaylord U.S. Pat. No. 3,995,099;Schueler, P. E.; Rhodes, Y. E. J. Org. Chem. 1974, 39, 2063-9; Ishitobi,H.; Tanida, H; Tsuji, T. Bull. Chem. Soc. Japan 1971, 44, 2993-3000;Stájer, G.; Virág, M.; Szabó, A. E.; Bernáth, G.; Sohár, P.; Sillanpää,R. Acta. Chem. Scand. 1996, 50, 922-30; Hart, H.; Ghosh, T. TetrahedronLett. 1988,29,881-884; Kato, M.; Yamamoto, S.; Yoshihara, T.; Furuichi,K; Miwa, T. Chem. Lett. 1987, 1823-1826; Kottwitz, J.; Vorbrüggen, H.Synthesis 1995, 636-637; Creary, X. J. Org. Chem. 1975, 40, 3326-3331;Alder, K.; Ache, H.-J.; Flock, F. H. Chem. Ber. 1960, 93, 1888-1895;Toder, B. H.; Branca, S. J.; Dieter, R. K.; Smith, A. B. III Synth.Commun. 1975, 5, 435-439; Sprague, P. W.; Heikes, J. E.; Gougoutas, J.Z.; Malley, M. F.; Harris, D. N.; and/or Greenberg, R. J. Med. Chem.1985, 28, 1580-1590.

The aforementioned approach(es) can be applied in a combinatorialfashion, for example, by utilizing a multi-well reaction block such asis described in Waldemar Ruediger, Wen-Jeng Li, John W., Allen Jr., andHarold N. Weller III, U.S. Pat. No. 5,961,925, Apparatus for Synthesisof Multiple Organic Compounds With Pinch Valve Block (incorporatedherein by reference in its entirety). By utilizing the above-mentionedmulti-well reaction block, one can, for example, perform multiples of 96reactions at a time. Solvent can then be removed from the reaction tubeswithout removal from the reaction block and the crude products can beprecipitated using a base such as sodium bicarbonate. The precipitatescan be collected by filtration of the reaction block and then thedesired products can be transferred directly to 96 well plates forscreening. In this fashion, a large array of compounds of formula I canbe synthesized, and tests conducted as desired by an automated approach.

Scheme III describes a method for preparing an intermediate compound offormula VI which can be used to synthesize a compound of formula I, asdescribed in Scheme II. As described in Scheme III, a diene of formulaII can be reacted with a dieneophile of formula VII to yield theintermediate of formula VI. The methods applied to obtain such atransformation are analogous to those described in Scheme I.

Scheme IV describes a method for preparing an intermediate compound offormula VI which can be used to synthesize a compound of formula I, asdescribed in Scheme II. As shown in Scheme IV, a diene of formula II canbe reacted with a dieneophile of formula VIII to yield the intermediateof formula IX. The intermediate of formula IX can be dehydrated to ananhydride-like intermediate of formula VI. Dehydration of the bis-acidintermediate of formula IX to can be achieved by a variety of methods,such as those known to one skilled in the art and described in thefollowing documents and the references embodied therein: Sprague et al.,J. Med. Chem. 28, 1580-1590 (1985); and/or Retemi et al., J. Org. Chem.61, 6296-6301 (1996).

Schemes I to IV describe general methods for the synthesis of compoundsof formula I, and intermediates thereof, in which substitution about thering system is incorporated directly, for example, at the level of theintermediate diene, dienophile, anhydride-like intermediate and aminegroups. In addition to these approaches, additional substitution can beincorporated onto an already-prepared compound of formula I by a varietyof approaches to prepare other compounds of the formula I. Exemplarymethods for further substitution are described in Schemes V to XI.

Scheme V describes one such approach to incorporating additionalsubstitution into a structure of formula I. As illustrated in Scheme V,a compound of formula X, which is a compound of formula I where A₁ andA₂ are CR⁷, W is NH—CHR⁷ and Y is CHR⁷—CHR⁷, can be functionalized atthe free amine of the group W by reaction with any of a variety ofelectrophilic agents such as acid halides or alkyl halides in thepresence of base, for example, by methods known by one skilled in theart. In Scheme V, X is a leaving group, and a compound of formula XI isa compound of formula I where A₁ and A₂ are CR⁷, W is NR⁷—HR⁷ and Y isCHR⁷—CHR⁷.

Scheme VI describes an additional approach for further incorporatingsubstitution onto a compound of formula I. As illustrated in Scheme VI,a compound of formula XII, which is a compound of formula I where A₁ andA₂ are CR⁷, W is S—CHR⁷ and Y is CHR⁷—CHR⁷, can be partially oxidizedwith an oxidizing agent such as mCPBA or other agents such as thoseknown to one skilled in the art, to give the sulfoxide analog of formulaXIII, which is a compound of formula I where A₁ and A₂ are CR⁷, W isSO—CHR⁷ and Y is CHR⁷—CHR⁷. Further treatment of a compound of formulaXIII with an oxidizing agent such as mCPBA or other agents such as thoseknown to one skilled in the art, can yield the sulphone analog offormula XIV, which is a compound of formula I where A₁ and A₂ are CR⁷, Wis SO₂—CHR⁷ and Y is CHR⁷—CHR⁷. Alternatively, a compound of formula XIIcan be converted directly to a compound of formula XIV by prolongedtreatment with an oxidizing agent, such as mCPBA, or with other agentssuch as those known to one skilled in the art.

Scheme VII describes another approach to incorporating additionalsubstitution onto a compound of formula I. As illustrated in Scheme VII,a diene of formula IIa can be reacted with a dienophile of formula III,as described in Scheme I, to yield a compound of formula IVa, which is acompound of formula I where Y is O, A₂ is CR⁷ and A₁ is C+CH₂)_(q)—T.The compound of formula IVa can be reacted with a reagent of formulaR¹²—T′ to obtain a compound of formula IVb or IVc which are compounds offormula I where Y is O, A₂ is CR⁷ and A₁ is C—(CH₂)_(q)—T′—R¹² orC—(CH₂)_(q)—T—R¹², respectively. The reagent R¹²—T′ can be obtained fromcommercial sources or can readily be prepared by one skilled in the art.

In the above Scheme, R¹² has the same definition as R⁷ defined earlier,q is zero or an integer from 0-8, and T is defined either as (1) anucleophilic center such as, but not limited, to a nitrogen, oxygen orsulfur-containing group, capable of undergoing a nucleophilicsubstitution reaction with the leaving group T′ or (2) a leaving groupcapable undergoing a nucleophilic substitution reaction with anucleophilic group T′ (such as, but not limited, to a nitrogen, oxygenor sulfur-containing nucleophilic group). T′ has the same definition asT. In the present case, for example, a nucleophilic substitutionreaction occurs when the attacking reagent (the nucleophile) brings anelectron pair to the substrate, using this pair to form the new bond,and the leaving group (the nucleofuge) comes away with the electronpair, leaving as an anionic intermediate. For a detailed discussion ofthe mechanism of aliphatic nucleophilic substitutions and a review ofspecific aliphatic nucleophilic substitution reactions see AdvancedOrganic Chemistry, Reactions, Mechanisms, and Structure, 4^(th)Addition. Jerry March (Ed.), John Wiley & Sons, New York (1992) 293-500and the references therein. Compounds of the formulae IVa, IVb, or IVcmay, of course, be employed in the methods described herein (especially,in the treatment of nuclear hormone receptor-associated conditions)without undergoing further reaction of T or T′.

An alternate approach to compounds of formula IVa, IVb and IVc isillustrated in Scheme VIII. For this approach, techniques such as thosedescribed in Schemes II, III and IV can be applied to the preparation ofan intermediate of formula VIa, where T and q are as defined in SchemeVII. The intermediate of formula VIa can be reacted with a substitutedamine of formula V, as described in Scheme II, to yield the compound offormula IVa, which is a compound of formula I where Y is O, A₂ is CR⁷and A₁ is C—(CH₂)_(q)—T. The compound of formula IVa can be treated inthe manner described in Scheme VII to obtain compounds of formula IVb orIVc which are compounds of formula I where Y is O, A₂ is CR⁷ and A₁ isC—(CH₂)_(q)—T′—R¹² or C—(CH₂)_(q)—T—R¹², respectively.

Scheme IX describes another approach to incorporating furthersubstitution onto a compound of formula I. As illustrated in Scheme IX(where X is a leaving group), a diene of formula IIb can be reacted witha dienophile of formula III, as described in Scheme I, to yield acompound of formula IVe, which is a compound of formula I where Y is NH,and A₁ and A₂ are CR⁷. The compound of formula IVe can be functionalizedat the free amine by reacting with a variety of electrophilic agentssuch as acid halides or alkyl halides in the presence of base, forexample by methods known by one skilled in the art and described inScheme V, to yield a compound of formula IVf, which is a compound offormula I where Y is NR⁷ and A₁ and A₂ are CR⁷.

An alternate approach to compounds of formula IVe and IVf is illustratedin Scheme X. For this approach, techniques as described in Schemes II,III and IV can be applied to the preparation of an intermediate offormula VIb. The intermediate of formula VIb can be reacted with asubstituted amine of formula V, as described in Scheme II, to yield acompound of formula IVe, which is a compound of formula I where Y is NH,and A₁ and A₂ are CR⁷. The latter intermediate can be treated in themanner described in Scheme V to obtain a compound of formula IVf, whichis a compound of formula I where Y is NR⁷, and A₁ and A₂ are CR⁷.

Scheme XI describes another approach to incorporating additionalsubstitution onto a compound of formula I. As illustrated in Scheme XI,a diene of formula IIc can be reacted with a dienophile of formula III,as described in Scheme I, to yield a compound of formula IVg, which is acompound of formula I where Y is SO and A₁ and A₂ are CR⁷. A compound offormula IVg can be treated with an oxidizing agent such as mCPBA, asdescribed in Scheme VI, to yield a compound of formula IVh, which is acompound of formula I where Y is SO₂ and A₁ and A₂ are CR⁷.

Scheme XII describes another approach to incorporating additionalsubstitution onto a compound of formula I. As illustrated in Scheme XII,a compound of formula XV, which can be prepared in accordance with theabove Schemes, can be incubated in the presence of a suitable enzyme ormicroorganism resulting in the formation of a hydroxylated analog offormula XVI. Such a process can be employed to yield regiospecific aswell as enantiospecific incorporation of a hydroxyl group into amolecule of formula XV by a specific microorganism or by a series ofdifferent microorganisms. Such microorganisms can, for example, bebacterial, yeast or fungal in nature and can be obtained fromdistributors such as ATCC or identified for use in this method such asby methods known to one skilled in the art. Compound XVI is a compoundof formula I where Y is as described above and A₁ and A₂ are preferablyCR⁷.

Scheme XIII describes another approach to incorporating additionalsubstitution onto a compound of formula I. As illustrated in SchemeXIII, a compound of formula XVII, which can be prepared in accordancewith the above Schemes, can be incubated in the presence of a suitableenzyme or microorganism resulting in the formation of a diol analog offormula XVIII. Such a process can be employed to yield regiospecific aswell as enantiospecific transformation of a compound of formula XVII toa 1-2 diol of formula XVIII by a specific microorganism or by a seriesof different microorganisms. Such microorganisms can, for example, bebacterial, yeast or fungal in nature and can be obtained fromdistributors such as ATCC or identified for use in this method such asby methods known to one skilled in the art. Compound XVIII is a compoundof formula I where Y is as described above and A₁ and A₂ are preferablyCR⁷.

The present invention also provides the methods of Schemes XII and XIII.

Thus, in one embodiment, the present invention provides a method forpreparation of a compound of the following formula XVI, or salt thereof:

where the symbols are as defined herein,comprising the steps of contacting a compound of the following formulaXV, or salt thereof:

where the symbols are as defined above;with an enzyme or microorganism capable of catalyzing the hydroxylationof said compound XV to form said compound XVI, and effecting saidhydroxylation.

In another preferred embodiment, the present invention provides a methodfor preparation of a compound of the following formula XVIII, or saltthereof:

where the symbols are as defined herein,comprising the steps of contacting a compound of the following formulaXVII, or salt thereof:

where the symbols are as defined above;with an enzyme or microorganism capable of catalyzing the opening of theepoxide ring of compound XVII to form the diol of said compound XVIII,and effecting said ring opening and diol formation.

All stereoconfigurations of the unspecified chiral centers of thecompounds of the formulae XV, XVI, XVII and XVIII are contemplated inthe methods of the present invention, either alone (that is,substantially free of other stereoisomers) or in admixture with otherstereoisomeric forms. Conversion of one isomer selectively (e.g.,hydroxylation of the exo isomer preferentially to hydroxylation of theendo isomer) when contacting an isomeric mixture is a preferredembodiment of the invention. Conversion to one isomer selectively (e.g.,hydroxylation on the exo face “exo isomer” preferentially to the endoface “endo isomer” or regioselective opening of an epoxide to form onlyone of two possible regioisomers of a trans diol) is a preferredembodiment of the invention. Hydroxylation of an achiral intermediate toform a single optical isomer of the hydroxylated product is also apreferred embodiment of the invention. Resolution of a recemic mixtureof an intermediate by selective hydroxylation, or epoxide ring openingand diol formation, to generate one of the two possible optical isomersis also a preferred embodiment of the invention. The term “resolution”as used herein denotes partial, as well as, preferably, completeresolution.

The terms “enzymatic process” or “enzymatic method”, as used herein,denote a process or method of the present invention employing an enzymeor microorganism. The term “hydroxylation”, as used herein, denotes theaddition of a hydroxyl group to a methylene group as described above.Hydroxylation can be achieved, for example, by contact with molecularoxygen according to the methods of the present invention. Diol formationcan be achieved, for example, by contact with water according to themethods of the present invention. Use of “an enzyme or microorganism” inthe present methods includes use of two or more, as well as a single,enzyme or microorganism.

The enzyme or microorganism employed in the present invention can be anyenzyme or microorganism capable of catalyzing the enzymatic conversionsdescribed herein. The enzymatic or microbial materials, regardless oforigin or purity, can be employed in the free state or immobilized on asupport such as by physical adsorption or entrapment. Microorganisms orenzymes suitable for use in the present invention can be selected byscreening for the desired activity, for example, by contacting acandidate microorganism or enzyme with a starting compound XV or XVII orsalt thereof, and noting conversion to the corresponding compound XVI orXVIII or salt thereof. The enzyme may, for example, be in the form ofanimal or plant enzymes or mixtures thereof, cells of microorganisms,crushed cells, extracts of cells, or of synthetic origin.

Exemplary microorganisms include those within the genera: Streptomycesor Amycolatopsis. Particularly preferred microorganisms are those withinthe species Streptomyces griseus, especially Streptomyces griseus ATCC10137, and Amycolatopsis orientalis such as ATCC 14930, ATCC 21425, ATCC35165, ATCC 39444, ATCC 43333, ATCC 43490, ATCC 53550, ATCC 53630, andespecially ATCC 43491. The term “ATCC” as used herein refers to theaccession number of the American Type Culture Collection, 10801University Blvd., Manassas Va. 20110-2209, the depository for theorganism referred to. It should be understood that mutants of theseorganisms are also contemplated by the present invention, for use in themethods described herein, such as those modified by the use of chemical,physical (for example, X-rays) or biological means (for example, bymolecular biology techniques).

Preferred enzymes include those derived from microorganisms,particularly those microorganisms described above. Enzymes may beisolated, for example, by extraction and purification methods such as bymethods known to those of ordinary skill in the art. An enzyme may, forexample, be used in its free state or in immobilized form. Oneembodiment of the invention is that where an enzyme is adsorbed onto asuitable carrier, e.g., diatomaceous earth (porous Celite HyfloSupercel), microporous polypropylene (Enka Accurel® polypropylenepowder), or a nonionic polymeric adsorbent such as Amberlite® XAD-2(polystyrene) or XAD-7 (polyacrylate) from Rohm and Haas Co. Whenemployed to immobilize an enzyme, a carrier may control the enzymeparticle size and prevent aggregation of the enzyme particles when usedin an organic solvent. Immobilization can be accomplished, for example,by precipitating an aqueous solution of the enzyme with cold acetone inthe presence of the Celite Hyflo Supercel followed by vacuum drying, orin the case of a nonionic polymeric adsorbent, incubating enzymesolutions with adsorbent on a shaker, removing excess solution anddrying enzyme-adsorbent resins under vacuum. While it is desirable touse the least amount of enzyme possible, the amount of enzyme requiredwill vary depending upon the specific activity of the enzyme used.

Hydroxylation as described above can occur in vivo. For example, liverenzyme can selectively, relative to the endo isomer, hydroxylate the exoisomer of a compound of the present invention. In conducting the methodsof the present invention outside the body, liver microsomal hydroxylasecan be employed as the enzyme for catalysis.

These processes may also be carried out using microbial cells containingan enzyme having the ability to catalyze the conversions. When using amicroorganism to perform the conversion, these procedures areconveniently carried out by adding the cells and the starting materialto the desired reaction medium.

Where microorganisms are employed, the cells may be used in the form ofintact wet cells or dried cells such as lyophilized, spray-dried orheat-dried cells, or in the form of treated cell material such asruptured cells or cell extracts. Cell extracts immobilized on Celite® orAccurel® polypropylene as described earlier may also be employed. Theuse of genetically engineered organisms is also contemplated. The hostcell may be any cell, e.g. Escherichia coli, modified to contain a geneor genes for expressing one or more enzymes capable of catalysis asdescribed herein.

Where one or more microorganisms are employed, the enzymatic methods ofthe present invention may be carried out subsequent to the fermentationof the microorganism (two-stage fermentation and conversion), orconcurrently therewith, that is, in the latter case, by in situfermentation and conversion (single-stage fermentation and conversion).

Growth of the microorganisms can be achieved by one of ordinary skill inthe art by the use of an appropriate medium. Appropriate media forgrowing microorganisms include those which provide nutrients necessaryfor the growth of the microbial cells. A typical medium for growthincludes necessary carbon sources, nitrogen sources, and elements (e.g.in trace amounts). Inducers may also be added. The term “inducer”, asused herein, includes any compound enhancing formation of the desiredenzymatic activity within the microbial cell.

Carbon sources can include sugars such as maltose, lactose, glucose,fructose, glycerol, sorbitol, sucrose, starch, mannitol, propyleneglycol, and the like; organic acids such as sodium acetate, sodiumcitrate, and the like; and alcohols such as ethanol, propanol and thelike.

Nitrogen sources can include N—Z amine A, corn steep liquor, soy beanmeal, beef extracts, yeast extracts, molasses, baker's yeast, tryptone,nutrisoy, peptone, yeastamin, amino acids such as sodium glutamate andthe like, sodium nitrate, ammonium sulfate and the like.

Trace elements can include magnesium, manganese, calcium, cobalt,nickel, iron, sodium and potassium salts. Phosphates may also be addedin trace or, preferably, greater than trace amounts.

The medium employed can include more than one carbon or nitrogen sourceor other nutrient.

Preferred media for growth include aqueous media.

The agitation and aeration of the reaction mixture affects the amount ofoxygen available during the conversion process when conducted, forexample, in shake-flask cultures or fermentor tanks during growth ofmicroorganisms.

Incubation of the reaction medium is preferably at a temperature betweenabout 4 and about 60° C. The reaction time can be appropriately varieddepending upon the amount of enzyme used and its specific activity.Reaction times may be reduced by increasing the reaction temperatureand/or increasing the amount of enzyme added to the reaction solution.

It is also preferred to employ an aqueous liquid as the reaction medium,although an organic liquid, or a miscible or immiscible (biphasic)organic/aqueous liquid mixture, may also be employed. The amount ofenzyme or microorganism employed relative to the starting material isselected to allow catalysis of the enzymatic conversions of the presentinvention.

Solvents for the organic phase of a biphasic solvent system may be anyorganic solvent immiscible in water, such as toluene, cyclohexane,xylene, trichlorotrifluoroethane and the like. The aqueous phase isconveniently of water, preferably deionized water, or a suitable aqueousbuffer solution, especially a phosphate buffer solution. The biphasicsolvent system preferably comprises between about 10 to 90 percent byvolume of organic phase and between about 90 to 10 percent by volume ofaqueous phase, and most preferably contains at or about 20 percent byvolume of organic phase and at or about 80 percent by volume of theaqueous phase.

An exemplary embodiment of such processes starts with preparation of anaqueous solution of the enzyme(s) or microbes to be used. For example,the preferred enzyme(s) or microbes can be added to a suitable amount ofan aqueous solvent, such as phosphate buffer or the like. This mixtureis preferably adjusted to and maintained at a desired pH.

The compounds XVI and XVIII produced by the processes of the presentinvention can be isolated and purified, for example, by methods such asextraction, distillation, crystallization, and column chromatography.

Preferred Compounds

A preferred subgenus of the compounds of the present invention includescompounds of the formula I or salts thereof wherein one or more,preferably all, of the following substituents are as defined below:

-   G is an aryl or heterocyclo (e.g., heteroaryl) group, where said    group is mono- or polycyclic, and which is optionally substituted at    one or more positions, preferably with hydrogen, alkyl or    substituted alkyl, alkenyl or substituted alkenyl, alkynyl or    substituted alkynyl, halo, cycloalkyl or substituted cycloalkyl,    cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl,    heterocyclo or substituted heterocyclo, arylalkyl or substituted    arylalkyl, heterocycloalkyl or substituted heterocycloalkyl, CN,    R¹OC═O, R¹C═O, R¹HNC═O, R¹R²NC═O, HOCR³R^(3′), nitro, R¹OCH₂, R¹O,    NH₂, NR⁴R⁵, S═OR¹, SO₂R¹, SO₂NR¹R^(1′), (R¹)(R^(1′))P═O, or    (R^(1′))(NHR¹)P═O;-   Z₁ is O, S, NH, or NR⁶;-   Z₂ is O, S, NH, or NR⁶;-   A₁ is CR⁷ or N;-   A₂ is CR⁷ or N;-   Y is J—J′—J″ where J is (CR⁷R^(7′))n and n=0-3, J′ is a bond or O,    S, S═O, SO₂, NH, OC═O, C═O, NR⁷, CR⁷R^(7′), R²P═O, R²P═S, R²P═O,    R²NHP═O, OP═OOR², OP═ONHR², OP═OR², OSO₂, NHNH, NHNR⁶, NR⁶NH, N═N,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, or heterocyclo or substituted heterocyclo, and J″ is    (CR⁷R^(7′))n and n=0-3, where Y is not a bond;-   W is CR⁷R^(7′)—R⁷R^(7′), CR⁷R^(7′)—C═O, NR⁹—CR⁷R^(7′), N═CR⁸, N═N,    NR⁹—NR^(9′), cycloalkyl or substituted cycloalkyl, cycloalkenyl or    substituted cycloalkenyl, heterocyclo or substituted heterocyclo, or    aryl or substituted aryl, wherein, when W is not NR⁹—CR⁷R^(7′),    N═CR⁸, N═N, NR⁹—NR^(9′), or heterocyclo or substituted heterocyclo,    then J′ must be O, S, S═O, SO₂, NH, NR⁷, OP═OOR², OP═ONHR², OSO₂,    NHNH, NHNR⁶, NR⁶NH, or N═N;-   Q₁ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl,    arylalkyl or substituted arylalkyl, alkynyl or substituted alkynyl,    aryl or substituted aryl, heterocyclo (e.g., heteroaryl) or    substituted heterocyclo (e.g., substituted heteroaryl), halo, CN,    R¹OC═O, R⁴C═O, R⁵R⁶NC═O, HOCR⁷R^(7′), nitro, R¹OCH₂, R¹O, NH₂, or    NR⁴R⁵;-   Q₂ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl,    arylalkyl or substituted arylalkyl, alkynyl or substituted alkynyl,    aryl or substituted aryl, heterocyclo (e.g., heteroaryl) or    substituted heterocyclo (e.g., substituted heteroaryl), halo, CN,    R¹OC═O, R⁴C═O, R⁵R⁶NC═O, HOCR⁷R^(7′), nitro, R¹OCH₂, R¹O, NH₂, or    NR⁴R⁵;-   L is a bond, (CR⁷R^(7′))n, NH, NR⁵ or NR⁵(CR⁷R^(7′))n, where n=0-3;-   R¹ and R^(1′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl;-   R² is alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl;-   R³ and R^(3′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, halo, CN, hydroxylamine, hydroxamide, alkoxy or    substituted alkoxy, amino, NR¹R², thiol, alkylthio or substituted    alkylthio;-   R⁴ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, R¹C═O,    R¹NHC═O, or SO₂NR¹R^(1′);-   R⁵ is alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, R¹C═O,    R¹NHC═O, SO₂R¹, or SO₂NR¹R^(1′);-   R⁶ is alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, CN, OH, OR¹,    R¹C═O, R¹NHC═O, SO₂R¹, or SO₂NR¹R^(1′);-   R⁷ and R^(7′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, halo, CN, OR⁴, nitro, hydroxylamine, hydroxylamide,    amino, NHR⁴, NR²R⁵, NOR¹, thiol, alkylthio or substituted alkylthio,    R¹C═O, R¹(C═O)O, R¹OC═O, R¹NHC═O, SOR¹, PO₃R¹R^(1′), R¹R^(1′)NC═O,    C═OSR¹, SO₂R¹, or SO₂NR¹R^(1′);-   R⁸ and R^(8′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, nitro, halo, CN, OR¹, amino, NHR⁴, NR²R⁵, NOR¹, alkylthio    or substituted alkylthio, C═OSR¹, R¹OC═O, R¹C═O, R¹NHC═O,    R¹R^(1′)NC═O, S═OR¹, SO₂R¹, PO₃R¹R^(1′), or SO₂NR¹R^(1′);-   R⁹ and R^(9′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl;    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, CN, OH, OR¹, R¹C═O, R¹OC═O, R¹NHC═O, or SO₂NR¹R^(1′);-   especially where the groups W and Y of this preferred subgenus are    also within the definitions of W′ and Y′ of formula Ia, with the    provisos (1) to (14) of said formula Ia where appropriate to this    subgenus, and most preferably where (i) when Y′ is —O— and W′ is    CR⁷R^(7′)—CR⁷R^(7′), A₁ and A₂ are not simultaneously CH; and (ii)    when L is a bond, G is not an unsubstituted phenyl group.

Another, more preferred subgenus of the compounds of the inventionincludes compounds of the formula I or salts thereof wherein one ormore, preferably all, of the following substituents are as definedbelow:

-   G is an aryl or heterocyclo (e.g., heteroaryl) group, where said    group is mono- or polycyclic, and which is optionally substituted at    one or more positions, preferably with hydrogen, alkyl or    substituted alkyl, alkenyl or substituted alkenyl, alkynyl or    substituted alkynyl, halo, cycloalkyl or substituted cycloalkyl,    cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl,    heterocyclo or substituted heterocyclo, arylalkyl or substituted    arylalkyl, heterocycloalkyl or substituted heterocycloalkyl, CN,    R¹C═O, R¹HNC═O, R¹R²NC═O, HOCR³R^(3′), nitro, R¹OCH₂, R¹O, NH₂,    NR⁴R⁵, SO₂R¹, or SO₂NR¹R^(1′);-   Z₁ is O;-   Z₂ is O;-   A₁ is CR⁷;-   A₂ is CR⁷;-   Y is J—J′—J″ where J is (CR⁷R^(7′))n and n=0-3, J′ is a bond or O,    S, S═O, SO₂, NH, NR⁷, CR⁷R^(7′), R²P═O, R²P═S, R²OP—O, R²NHP═O,    OP═OOR², OP═ONHR², OP═OR², OSO₂, NHNH, NHNR⁶, NR⁶NH, N═N, cycloalkyl    or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl,    or heterocyclo or substituted heterocyclo, and J″ is (CR⁷R^(7′))n    and n=0-3, where Y is not a bond;-   W is CR⁷R^(7′)—CR⁷R^(7′), CR⁷R^(7′)—C═O, NR⁹—CR⁷R^(7′), N═CR⁸, N═N,    NR⁹—NR^(9′), cycloalkyl or substituted cycloalkyl, cycloalkenyl or    substituted cycloalkenyl, heterocyclo or substituted heterocyclo, or    aryl or substituted aryl, wherein, when W is not NR⁹—CR⁷R^(7′),    N═CR⁸, N═N, NR⁹—NR^(9′), or heterocyclo or substituted heterocyclo,    then J′ must be O, S, S═O, SO₂, NH, NR⁷, OP═OOR², OP═ONHR², OSO₂,    NHNH, NHNR⁶, NR⁶NH, or N═N;-   Q₁ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl,    arylalkyl or substituted arylalkyl, alkynyl or substituted alkynyl,    aryl or substituted aryl, heterocyclo (e.g., heteroaryl) or    substituted heterocyclo (e.g., substituted heteroaryl), halo, CN,    R⁴C═O, R⁵R⁶NC═O, HOCR⁷R^(7′), nitro, R¹OCH₂, R¹O, NH₂, or NR⁴R⁵;-   Q₂ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl,    arylalkyl or substituted arylalkyl, alkynyl or substituted alkynyl,    aryl or substituted aryl, heterocyclo (e.g., heteroaryl) or    substituted heterocyclo (e.g., substituted heteroaryl), halo, CN,    R⁴C═O, R⁵R⁶NC═O, HOCR⁷R^(7′), nitro, R¹OCH₂, R¹O, NH₂, or NR⁴R⁵;-   L is a bond;-   R¹ and R^(1′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl;-   R² is alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl;-   R³ and R^(3′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, halo, CN, alkoxy or substituted alkoxy, amino, NR¹R²,    alkylthio or substituted alkylthio;-   R⁴ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, R¹C═O,    R¹NHC═O, or SO₂NR¹R^(1′);-   R⁵ is alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, R¹C═O,    R¹NHC═O, SO₂R¹, or SO₂NR¹R^(1′);-   R⁶ is alkyl or substituted alkyl, alkenyl or substituted alkenyl,    alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or    substituted heterocyclo, cycloalkylalkyl or substituted    cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl,    heterocycloalkyl or substituted heterocycloalkyl, aryl or    substituted aryl, arylalkyl or substituted arylalkyl, CN, OH, OR¹,    R¹C═O, R¹NHC═O, SO₂R¹, or SO₂NR¹R^(1′);-   R⁷ and R^(7′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, halo, CN, OR⁴, nitro, amino, NHR⁴, NR²R⁵, alkylthio or    substituted alkylthio, R¹C═O, R¹(C═O)O, R1NHC═O, SO₂R¹,    R¹R^(1′)NC═O, or SO₂NR¹R^(1′);-   R⁸ and R^(8′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, nitro, halo, CN, OR¹, amino, NHR⁴, NR²R⁵, alkylthio or    substituted alkylthio, R¹C═O, R¹NHC═O, R¹R^(1′)NC═O, SO₂R¹, or    SO₂NR¹R^(1′); and-   R⁹ and R^(9′) are each independently H, alkyl or substituted alkyl,    alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,    cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted    cycloalkenyl, heterocyclo or substituted heterocyclo,    cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or    substituted cycloalkenylalkyl, heterocycloalkyl or substituted    heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted    arylalkyl, CN, OH, OR¹, R¹C═O, R¹NHC═O, or SO₂NR¹R^(1′);-   especially where the groups W and Y of this preferred subgenus are    also within the definitions of W′ and Y′of formula Ia, with the    provisos (1) to (14) of said formula Ia where appropriate to this    subgenus, and most preferably where (i) when Y′ is —O— and W′ is    CR⁷R^(7′)—CR⁷R^(7′), A₁ and A₂ are not simultaneously CH; and (ii)    when L is a bond, G is not an unsubstituted phenyl group.

A particularly preferred subgenus of the compounds of the inventionincludes compounds of the formula I or salts thereof wherein one ormore, preferably all, of the substituents are as defined below:

-   G is an aryl (especially, phenyl or naphthyl) or heterocyclo    (especially those heterocyclo groups G of the compounds of the    Examples herein) group, where said group is mono- or polycyclic, and    which is optionally substituted at one or more positions, preferably    with substituents as exemplified in any of the compounds of the    Examples herein;-   L is a bond, (CR⁷R^(7′))n (where n is 1 and R⁷ and R^(7′) are each    independently H, alkyl or substituted alkyl), or —CH₂—NH—;-   A₁ and A₂ are each independently CR⁷ where R⁷ (i) is hydrogen, alkyl    or substituted alkyl, arylalkyl or substituted arylalkyl, alkenyl or    substituted alkenyl (for example, alkenyl substituted with aryl    (especially, phenyl or naphthyl) or substituted aryl, or alkenyl    substituted with heterocyclo or substituted heterocyclo), aryl or    substituted aryl, heterocyclo or substituted heterocyclo,    heterocycloalkyl or substituted heterocycloalkyl, where, for each,    preferred substituents are one or more groups selected from V¹    (especially A₁ and A₂ groups of the formula CR⁷ where R⁷ for each of    A₁ and/or A₂ is independently selected from unsubstituted C₁₋₄    alkyl, or C₁₋₄ alkyl which alkyl is substituted by one or more    groups V₁), or (ii) forms, together with R⁷ of a group W (especially    where W is CR⁷R^(7′)—CR⁷R^(7′)), a heterocyclic ring;-   V¹ is OH, CN, halo, —O-aryl, —O-substituted aryl, —O-heterocyclo    (e.g., —O— (optionally substituted pyridinyl) or —O-(optionally    substituted pyrimidinyl)), —O-substituted heterocyclo, —O—CO-alkyl,    —O—CO-substituted alkyl, —O-(alkylsilyl), —O-arylalkyl,    —O-substituted arylalkyl, —O—CO-alkyl, —O—CO-substituted alkyl,    —O—CO-arylalkyl, —O—CO-substituted arylalkyl, —O—CO-aryl,    —O—CO-substituted aryl, —O—CO-heterocyclo, —O—CO-substituted    heterocyclo, —S-(optionally substituted aryl)-NH—CO-(optionally    substituted alkyl), —SO-(optionally substituted    aryl)-NH—CO-(optionally substituted alkyl), —SO2-(optionally    substituted aryl)-NH—CO-(optionally substituted alkyl),    —NH—SO₂-aryl, —NH—SO₂-substituted aryl, —NH—CO—O-(optionally    substituted arylalkyl), —NH—CO—O-alkyl, —NH—CO—O-substituted alkyl,    —NH—CO-alkyl, —NH—CO-substituted alkyl, —NH—CO-aryl,    —NH—CO-substituted aryl, —NH—CO-(optionally substituted arylalkyl),    —NH—CO-(optionally substituted alkyl)-O-(optionally substituted    aryl), —N(optionally substituted alkyl)(optionally substituted    aryl), —N(optionally substituted alkyl)(optionally substituted    arylalkyl), —COH, —COOH, —CO—O-alkyl, —CO—O-substituted alkyl,    —CO—O-optionally substituted arylalkyl, —CO-aryl, —CO-substituted    aryl, —O—CO—NH-aryl, —O—CO—NH-substituted aryl, —CO—NH-aryl,    —CO—NH-substituted aryl, —CO—NH-arylalkyl, —CO—NH-substituted    arylalkyl, —O-(optionally substituted aryl)-NH—CO-(optionally    substituted alkyl);-   Y is —O—, —SO—, —N(V²)—, —CH₂—N(V²)—, —CO—N(alkyl)-, —CH₂—S—,    —CH₂—SO₂—;-   V² is hydrogen, alkyl, arylalkyl, —CO-alkyl, —CO—O-aryl,    —CO—O-arylalkyl;-   W is CR⁷R^(7′)—CR⁷R^(7′) (where R⁷ and R^(7′) are each independently    selected from H, OH, alkyl or substituted alkyl (such as    hydroxyalkyl), or where R⁷ forms a heterocyclic ring together with    R⁷ of A₁ or A₂), CR⁸═CR^(8′) (where R⁸ and R^(8′) are each    independently selected from H, alkyl or substituted alkyl (such as    hydroxyalkyl)), CR⁷R^(7′)—C═O (where R⁷ and R^(7′) are each    hydrogen, or where R⁷ forms a heterocyclic ring together with R⁷ of    A₁ or A₂), N═CR⁸ (where R⁸ is alkyl), cycloalkyl or substituted    cyclalkyl, or heterocyclo or substituted heterocyclo;-   Z₁ and Z₂ are O; and-   Q₁ and Q₂ are H.

Preferred G—L groups are optionally substituted phenyl, optionallysubstituted naphthyl and optionally substituted fused bicyclicheterocyclic groups such as optionally substituted benzo-fusedheterocyclic groups (e.g., bonded to the remainder of the moleculethrough the benzene portion), especially such groups wherein theheterocyclic ring bonded to benzene has 5 members exemplified bybenzoxazole, benzothiazole, benzothiadiazole, benzoxadiazole orbenzothiophene, for example:

where

-   X=halo (especially F), OH, CN, NO₂ or

-   X′=halo (especially Cl, F, or I), CH₃, CF₃, CN or OCH₃;-   U is O or S (where S can optionally be oxygenated, e.g., to SO);-   U¹ is CH₃ or CF₃;-   each U² is independently N, CH or CF;-   U³ is N, O or S;-   U⁴ and U⁵, together with the atoms to which they are bonded, form an    optionally substituted 5-membered heterocyclic ring which can be    partially unsaturated or aromatic and which contains 1 to 3 ring    heteroatoms;-   each U⁶ is independently CH or N; and

denotes optional double bond(s) within the ring formed by U³, U⁴ and U⁵.

An especially preferred subgenus includes compounds of the formula Ihaving the following structure, or salts thereof:

where G is an optionally substituted phenyl, naphthyl or benzo-fusedbicyclic heterocyclic group, R⁷ is CH₃ or C₁₋₄alkyl substituted by V¹,and one R^(7′) is H or hydroxyl and the other is H.

Preferred compounds of the invention include:

-   [3aS-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aS-(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aS-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-methyl-2-pyridinecarbonitrile;-   [3aS-(3aα,4β,5β,7β,7aα)]-2-(2,1,3-Benzoxadiazol-5-yl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;-   [3aS-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3,4-dimethyl-2-pyridinecarbonitrile;-   [3aR-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3,4-dimethyl-2-pyridinecarbonitrile;-   [3aS-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;-   [3aR-(3aα,4β,5β,7β,7aα)]-2-(7-Chloro-2,1,3-benzoxadiazol-4-yl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;-   [3aR-(3aα,4β,5α,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;-   (3aα,4β,5α,6β,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-6-cyano-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic    acid, methyl ester;-   (3aα,4β,7β,7aα)-4-(Octahydro-4,7,8-trimethyl-1,3-dioxo-4,7-imino-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dichloro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aS-(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dichloro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;-   (3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[difluoromethyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[phenylmethoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[propyloxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[cyclopropylmethyloxy]carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[methoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2,3-dichlorobenzonitrile;-   [3aR-(3aα,4β,4aα,5aα,6β,7aα)]-4-(Octahydro-4a-hydroxy-4,6-dimethyl-1,3-dioxo-4,6-epoxycycloprop[f]isoindol-2(1H)-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-N,N-dimethyl-1H-isoindole-5-carboxamide;-   [3aR-(3aα,4β,5β,6β,7β,7aα)]-4-(Octahydro-5-chloro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aS-(3aα,4β,5β,6β,7β,7aα)]-4-(Octahydro-5-chloro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[5-chloro-2-pyridinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[[phenylamino]carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5a,7β,7aα)]-4-(Octahydro-5-[[(1-methylethyloxy)carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[5-fluoro-4-pyrimidinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[ethyloxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic    acid, 4-pyridinylmethyl ester;-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[4-pyridinylmethoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   3aα,4β,5β,7β,7aα)-4-(Octahydro-5-[[[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]oxy]methyl]-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic    acid, methyl ester;-   [3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-cyclopropylmethoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[((phenylmethyl)amino)carbonyl]oxy]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;    and-   [3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-cyclopropyloxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

or pharmaceutically acceptable salts, solvates, prodrugs orstereoisomers thereof.

More preferred compounds of the invention include:

-   [3aR-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;-   [3aS-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;-   [3aR-(3aαx,4β,5β,7β,7aα)]-2-(4-Chloro-3-iodophenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;-   [3aS-(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,7β,7aα)]-4-(Octahydro-4,7-dimethyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aS-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aS-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;-   [3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;-   [3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;-   [3aS-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-3-(trifluoromethyl)pyridinyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;-   [3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-methyl-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-methoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;-   [3aS-(3aα,4β,5β7β,7aα)]-4-(Octahydro-5-methoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aS-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,7β,7aα)]-5-(Octahydro-4,7-dimethyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;-   [3aS-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-2-methyl-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;-   [3aR-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-2-methyl-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;-   (3aα,4β,6β,7β,7aα)-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;

(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, methyl ester;

-   [3aS-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;

(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-ethylsulfonamido-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(4-fluorophenylamino)carbonyl]oxy]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(1-methylethylamino)carbonyl]oxy]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aS-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(1-methylethoxy)carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-N-methyl-N-phenyl-1H-isoindole-5-carboxamide;-   [3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-chloro-3-methylbenzonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[ethoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aS-(3aα,4β,5α,6β,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic    acid, methyl ester;

(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-methoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carbonitrile;-   [3aR-(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-methyl-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[[(cyclopropylmethyl)amino]carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(dimethylamino)sulfonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   (3aα,4β,5α,7β,7aα)-4-(Octahydro-5-benzenesulfonamido-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;-   [3aR-(3aα,4β,5α,6β,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic    acid, methyl ester; and-   [3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(dimethylamino)sulfonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;    or pharmaceutically acceptable salts, solvates, prodrugs or    stereoisomers thereof.

Compounds where R^(7′) is hydroxyl can provide enhanced water solubilityand metabolic stability, relative to the corresponding compounds whereR^(7′) is H, in addition to having good permeability and high systemicblood levels. These hydroxyl-bearing compounds can be obtained in vivoby metabolism of the corresponding compound where R^(7′) is H, as wellas by synthetic preparative methods such as those described herein.

Use and Utility

The compounds of the present invention modulate the function of nuclearhormone receptors (NHR), and include compounds which are, for example,agonists, partial agonists, antagonists or partial antagonists of theandrogen receptor (AR), the estrogen receptor (ER), the progesteronereceptor (PR), the glucocorticoid receptor (GR), the mineralocorticoidreceptor (MR), the steroid and xenobiotic receptor (SXR), other steroidbinding NHR's, the Orphan receptors or other NHR's. Selective modulationof one such NHR relative to others within the NHR family is preferred.“Modulation” includes, for example, activation (e.g., agonist activitysuch as selective androgen receptor agonist activity) or inhibition(e.g., antagonist activity).

The present compounds are thus useful in the treatment of NHR-associatedconditions. A “NHR-associated condition”, as used herein, denotes acondition or disorder which can be treated by modulating the function ofa NHR in a subject, wherein treatment comprises prevention (e.g.,prophylactic treatment), partial alleviation or cure of the condition ordisorder. Modulation may occur locally, for example, within certaintissues of the subject, or more extensively throughout a subject beingtreated for such a condition disorder.

The compounds of the present invention are useful for the treatment of avariety of conditions and disorders including, but not limited to, thosedescribed following:

Compounds of formula I can be applied as agonists, partial agonists,antagonists, or partial antagonists of the estrogen receptor, preferablyselectively to that receptor, in an array of medical conditions whichinvolve modulation of the estrogen receptor pathway. Applications ofsaid compounds include but are not limited to: osteoporosis, hotflushes, vaginal dryness, prostate cancer, breast cancer, endometrialcancer, cancers expressing the estrogen receptor such as theaforementioned cancers and others, contraception, pregnancy termination,menopause, amennoreahea, and dysmennoreahea.

Compounds of formula I can be applied as agonists, partial agonists,antagonists or partial antagonists of the progesterone receptor,preferably selectively to that receptor, in an array of medicalconditions which involve modulation of the progesterone receptorpathway. Applications of said compounds include but are not limited to:breast cancer, other cancers containing the progesterone receptor,endometriosis, cachexia, contraception, menopause, cyclesynchrony,meniginoma, dysmennoreahea, fibroids, pregnancy termination, laborinduction and osteoporosis.

Compounds of formula I can be applied as agonists, partial agonists,antagonists or partial antagonists of the glucocorticoid receptor,preferably selectively to that receptor, in an array of medicalconditions which involve modulation of the glucocorticoid receptorpathway. Applications of said compounds include but are not limited to:inflammatory diseases, autoimmune diseases, prostate cancer, breastcancer, Alzheimer's disease, psychotic disorders, drug dependence,non-insulin dependent Diabetes Mellitus, and as dopamine receptorblocking agents or otherwise as agents for the treatment of dopaminereceptor mediated disorders.

Compounds of formula I can be applied as agonists, partial agonists,antagonists or partial antagonists of the mineralocorticoid receptor,preferably selectively to that receptor, in an array of medicalconditions which involve modulation of the mineralocorticoid receptorpathway. Applications of said compounds include but are not limited to:drug withdrawal syndrome and inflammatory diseases.

Compounds of formula I can be applied as agonists, partial agonists,antagonists or partial antagonists of the aldosterone receptor,preferably selectively to that receptor, in an array of medicalconditions which involve modulation of the aldosterone receptor pathway.One application of said compounds includes but is not limited to:congestive heart failure.

Compounds of formula I can be applied as agonists, partial agonists,antagonists or partial antagonists of the androgen receptor, preferablyselectively to that receptor, in an array of medical conditions whichinvolve modulation of the androgen receptor pathway. Applications ofsaid compounds include but are not limited to: hirsutism, acne,seborrhea, Alzheimer's disease, androgenic alopecia, hypogonadism,hyperpilosity, benign prostate hypertrophia, adenomas and neoplasies ofthe prostate (such as advanced metastatic prostate cancer), treatment ofbenign or malignant tumor cells containing the androgen receptor such asis the case for breast, brain, skin, ovarian, bladder, lymphatic, liverand kidney cancers, pancreatic cancers modulation of VCAM expression andapplications therein for the treatment of heart disease, inflammationand immune modulations, modulation of VEGF expression and theapplications therein for use as antiangiogenic agents, osteoporosis,suppressing spermatogenesis, libido, cachexia, endometriosis, polycysticovary syndrome, anorexia, androgen supplement for age related decreasedtestosterone levels in men, male menopause, male hormone replacement,male and female sexual dysfunction, and inhibition of muscular atrophyin ambulatory patients. For example, pan AR modulation is contemplated,with prostate selective AR modulation (“SARM”) being particularlypreferred, such as for the treatment of early stage prostate cancers.

Compounds of formula I can be applied as (preferably, selective)antagonists of the mutated androgen receptor, for example, found in manytumor lines. Examples of such mutants are those found in representativeprostate tumor cell lines such as LNCap, (T877A mutation, Biophys. Acta,187, 1052 (1990)), PCa2b, (L701H & T877A mutations, J. Urol., 162, 2192(1999)) and CWR22, (H874Y mutation, Mol. Endo., 11, 450 (1997)).Applications of said compounds include but are not limited to: adenomasand neoplasies of the prostate, breast cancer and endometrial cancer.

Compounds of formula I can be applied as agonists, partial agonists,antagonists or partial antagonists of the steroid and xenobioticreceptor, preferably selectively to that receptor, in an array ofmedical conditions which involve modulation of the steroid andxenobiotic receptor pathway. Applications of said compounds include butare not limited to: treatment of disregulation of cholesterolhomeostasis, attenuation of metabolism of pharmaceutical agents byco-administration of an agent (compound of the present invention) whichmodulates the P450 regulator effects of SXR.

Along with the aforementioned NHR, there also exist a number of NHR forwhich the activating or deactivating ligands may not be characterized.These proteins are classified as NHR due to strong sequence homology toother NHR, and are known as the Orphan receptors. Because the Orphanreceptors demonstrate strong sequence homology to other NHR, compoundsof formula I include those which serve as modulators of the function ofthe Orphan NHR. Orphan receptors which are modulated by NHR modulatorssuch as compounds within the scope of formula I are exemplified, but notlimited to, those listed in Table 1. Exemplary therapeutic applicationsof modulators of said Orphan receptors are also listed in Table 1, butare not limited to the examples therein.

TABLE 1 Exemplary Orphan nuclear hormone receptors, form (M = monomeric,D = heterodimeric, H = homodimeric), tissue expression and targettherapeutic applications. (CNS = central nervous system) TargetTherapeutic Receptor Form Tissue Expression Application NURR1 M/DDopaminergic Neurons Parkinson's Disease RZRβ M Brain (Pituitary),Muscle Sleep Disorders RORα M Cerebellum, Purkinje Cells Arthritis,Cerebellar Ataxia NOR-1 M Brain, Muscle, Heart, CNS Disorders, Adrenal,Thymus Cancer NGFI-Bβ M/D Brain CNS Disorders COUP-Tfα H Brain CNSDisorders COUP-TFβ H Brain CNS Disorders COUP-TFγχ H Brain CNS DisordersNur77 H Brain, Thymus, Adrenals CNS Disorders Rev-ErbAα H Muscle, Brain(Ubiquitous) Obesity HNF4α H Liver, Kidney, Intestine Diabetes SF-1 MGonads, Pituitary Metabolic Disorders LXRα, β D Kidney (Ubiquitous)Metabolic Disorders GCNF M/H Testes, Ovary Infertility ERRα, β MPlacenta, Bone Infertility, Osteoporosis FXR D Liver, Kidney MetabolicDisorders CARα H Liver, Kidney Metabolic Disorders PXR H Liver,Intestine Metabolic Disorders COUP-TF2 D Testis Oncology/angiogenesis(ARP1) RORbeta M CNS, retina, pineal gland Metabolic Disorders

The present invention thus provides methods for the treatment ofNHR-associated conditions, comprising the step of administering to asubject in need thereof at least one compound of formula I in an amounteffective therefor. Other therapeutic agents such as those describedbelow may be employed with the inventive compounds in the presentmethods (for example, separately, or formulated together as a fixeddose). In the methods of the present invention, such other therapeuticagent(s) can be administered prior to, simultaneously with or followingthe administration of the compound(s) of the present invention.

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the formula I capable oftreating a NHR-associated condition in an amount effective therefor, anda pharmaceutically acceptable carrier (vehicle or diluent). Thecompositions of the present invention can contain other therapeuticagents as described below, and can be formulated, for example, byemploying conventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

It should be noted that the compounds of the present invention are,without limitation as to their mechanism of action, useful in treatingany of the conditions or disorders listed or described herein such asinflammatory diseases or cancers, or other proliferate diseases, and incompositions for treating such conditions or disorders. Such conditionsand disorders include, without limitation, any of those describedpreviously, as well as those described following such as: maintenance ofmuscle strength and function (e.g., in the elderly); reversal orprevention of frailty or age-related functional decline (“ARFD”) in theelderly (e.g., sarcopenia); treatment of catabolic side effects ofglucocorticoids; prevention and/or treatment of reduced bone mass,density or growth (e.g., osteoporosis and osteopenia); treatment ofchronic fatigue syndrome (CFS); chronic malagia; treatment of acutefatigue syndrome and muscle loss following elective surgery (e.g.,post-surgical rehabilitation); acceleration of wound healing;accelerating bone fracture repair (such as accelerating the recovery ofhip fracture patients); accelerating healing of complicated fractures,e.g. distraction osteogenesis; in joint replacement; prevention ofpost-surgical adhesion formation; acceleration of tooth repair orgrowth; maintenance of sensory function (e.g., hearing, sight, olfactionand taste); treatment of periodontal disease; treatment of wastingsecondary to fractures and wasting in connection with chronicobstructive pulmonary disease (COPD), chronic liver disease, AIDS,weightlessness, cancer cachexia, burn and trauma recovery, chroniccatabolic state (e.g., coma), eating disorders (e.g., anorexia) andchemotherapy; treatment of cardiomyopathy; treatment ofthrombocytopenia; treatment of growth retardation in connection withCrohn's disease; treatment of short bowel syndrome; treatment ofirritable bowel syndrome; treatment of inflammatory bowel disease;treatment of Crohn's disease and ulcerative colitis; treatment ofcomplications associated with transplantation; treatment ofphysiological short stature including growth hormone deficient childrenand short stature associated with chronic illness; treatment of obesityand growth retardation associated with obesity; treatment of anorexia(e.g., associated with cachexia or aging); treatment of hypercortisolismand Cushing's syndrome; Paget's disease; treatment of osteoarthritis;induction of pulsatile growth hormone release; treatment ofosteochondrodysplasias; treatment of depression, nervousness,irritability and stress; treatment of reduced mental energy and lowself-esteem (e.g., motivation/assertiveness); improvement of cognitivefunction (e.g., the treatment of dementia, including Alzheimer's diseaseand short term memory loss); treatment of catabolism in connection withpulmonary dysfunction and ventilator dependency; treatment of cardiacdysfunction (e.g., associated with valvular disease, myocardialinfarction, cardiac hypertrophy or congestive heart failure); loweringblood pressure; protection against ventricular dysfunction or preventionof reperfusion events; treatment of adults in chronic dialysis; reversalor slowing of the catabolic state of aging; attenuation or reversal ofprotein catabolic responses following trauma (e.g., reversal of thecatabolic state associated with surgery, congestive heart failure,cardiac myopathy, burns, cancer, COPD etc.); reducing cachexia andprotein loss due to chronic illness such as cancer or AIDS; treatment ofhyperinsulinemia including nesidioblastosis; treatment ofimmunosuppressed patients; treatment of wasting in connection withmultiple sclerosis or other neurodegenerative disorders; promotion ofmyelin repair; maintenance of skin thickness; treatment of metabolichomeostasis and renal homeostasis (e.g., in the frail elderly);stimulation of osteoblasts, bone remodeling and cartilage growth;regulation of food intake; treatment of insulin resistance, includingNIDDM, in mammals (e.g., humans); treatment of insulin resistance in theheart; improvement of sleep quality and correction of the relativehyposomatotropism of senescence due to high increase in REM sleep and adecrease in REM latency; treatment of hypothermia; treatment ofcongestive heart failure; treatment of lipodystrophy (e.g., in patientstaking HIV or AIDS therapies such as protease inhibitors); treatment ofmuscular atrophy (e.g., due to physical inactivity, bed rest or reducedweight-bearing conditions); treatment of musculoskeletal impairment(e.g., in the elderly); improvement of the overall pulmonary function;treatment of sleep disorders; and the treatment of the catabolic stateof prolonged critical illness; treatment of hirsutism, acne, seborrhea,androgenic alopecia, anemia, hyperpilosity, benign prostate hypertrophy,adenomas and neoplasies of the prostate (e.g., advanced metastaticprostate cancer) and malignant tumor cells containing the androgenreceptor, such as is the case for breast, brain, skin, ovarian, bladder,lymphatic, liver and kidney cancers; cancers of the skin, pancreas,endometrium, lung and colon; osteosarcoma; hypercalcemia of malignancy;metastatic bone disease; treatment of spermatogenesis, endometriosis andpolycystic ovary syndrome; counteracting preeclampsia, eclampsia ofpregnancy and preterm labor; treatment of premenstrual syndrome;treatment of vaginal dryness; age related decreased testosterone levelsin men, male menopause, hypogonadism, male hormone replacement, male andfemale sexual dysfunction (e.g., erectile dysfunction, decreased sexdrive, sexual well-being, decreased libido), male and femalecontraception, hair loss, Reaven's Syndrome and the enhancement of boneand muscle performance/strength; and the conditions, diseases, andmaladies collectively referenced to as “Syndrome X” or MetabolicSyndrome as detailed in Johannsson J. Clin. Endocrinol. Metab., 82,727-34 (1997).

The present compounds have therapeutic utility in the modulation ofimmune cell activation/proliferation, e.g., as competitive inhibitors ofintercellular ligand/receptor binding reactions involving CAMs (CellularAdhesion Molecules) and Leukointegrins. For example, the presentcompounds modulate LFA-ICAM 1, and are particularly useful as LFA-ICAM 1antagonists, and in the treatment of all conditions associated withLFA-ICAM 1 such as immunological disorders. Preferred utilities for thepresent compounds include, but are not limited to: inflammatoryconditions such as those resulting from a response of the non-specificimmune system in a mammal (e.g., adult respiratory distress syndrome,shock, oxygen toxicity, multiple organ injury syndrome secondary tosepticemia, multiple organ injury syndrome secondary to trauma,reperfusion injury of tissue due to cardiopulmonary bypass, myocardialinfarction or use with thrombolysis agents, acute glomerulonephritis,vasculitis, reactive arthritis, dermatosis with acute inflammatorycomponents, stroke, thermal injury, hemodialysis, leukopheresis,ulcerative colitis, necrotizing enterocolitis and granulocytetransfusion associated syndrome) and conditions resulting from aresponse of the specific immune system in a mammal (e.g., psoriasis,organ/tissue transplant rejection, graft vs. host reactions andautoimmune diseases including Raynaud's syndrome, autoimmunethyroiditis, dermatitis, multiple sclerosis, rheumatoid arthritis,insulin-dependent diabetes mellitus, uveitis, inflammatory bowel diseaseincluding Crohn's disease and ulcerative colitis, and systemic lupuserythematosus). The present compounds can be used in treating asthma oras an adjunct to minimize toxicity with cytokine therapy in thetreatment of cancers. The present compounds can be employed in thetreatment of all diseases currently treatable through steroid therapy.The present compounds may be employed for the treatment of these andother disorders alone or with other immunosuppressive orantiinflammatory agents. In accordance with the invention, a compound ofthe formula I can be administered prior to the onset of inflammation (soas to suppress an anticipated inflammation) or after the initiation ofinflammation. When provided prophylactically, the immunosuppressivecompound(s) are preferably provided in advance of any inflammatoryresponse or symptom (for example, prior to, at, or shortly after thetime of an organ or tissue transplant but in advance of any symptoms ororgan rejection). The prophylactic administration of a compound of theformula I prevents or attenuates any subsequent inflammatory response(such as, for example, rejection of a transplanted organ or tissue,etc.) Administration of a compound of the formula I attenuates anyactual inflammation (such as, for example, the rejection of atransplanted organ or tissue).

The compounds of the formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrasternal injection or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds can, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release can be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds canalso be administered liposomally.

Exemplary compositions for oral administration include suspensions whichcan contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which can contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I can also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations can also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g. Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which can contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which can contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid, or Cremaphor.

Exemplary compositions for rectal administration include suppositorieswhich can contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention can bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 1 to 100 (for example,15 or lower, especially 1 to 3 or less) mg/kg of body weight of activecompound per day, which can be administered in a single dose or in theform of individual divided doses, such as from 1 to 4 times per day. Itwill be understood that the specific dose level and frequency of dosagefor any particular subject can be varied and will depend upon a varietyof factors including the activity of the specific compound employed, themetabolic stability and length of action of that compound, the species,age, body weight, general health, sex and diet of the subject, the modeand time of administration, rate of excretion, drug combination, andseverity of the particular condition. Preferred subjects for treatmentinclude animals, most preferably mammalian species such as humans, anddomestic animals such as dogs, cats and the like, subject toNHR-associated conditions.

As mentioned above, the compounds of the present invention can beemployed alone or in combination with each other and/or other suitabletherapeutic agents useful in the treatment of NHR-associated conditions,e.g., an antibiotic or other pharmaceutically active material.

For example, the compounds of the present invention can be combined withgrowth promoting agents, such as, but not limited to, TRH,diethylstilbesterol, theophylline, enkephalins, E series prostaglandins,compounds disclosed in U.S. Pat. No. 3,239,345, e.g., zeranol, andcompounds disclosed in U.S. Pat. No. 4,036,979, e.g., sulbenox orpeptides disclosed in U.S. Pat. No. 4,411,890.

The compounds of the invention can also be used in combination withgrowth hormone secretagogues such as GHRP-6, GHRP-1 (as described inU.S. Pat. No. 4,411,890 and publications WO 89/07110 and WO 89/07111),GHRP-2 (as described in WO 93/04081), NN703 (Novo Nordisk), LY444711(Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, or with growthhormone releasing factor and its analogs or growth hormone and itsanalogs or somatomedins including IGF-1 and IGF-2, or withalpha-adrenergic agonists, such as clonidine or serotinin 5-HT_(D)agonists, such as sumatriptan, or agents which inhibit somatostatin orits release, such as physostigmine and pyridostigmine. A still furtheruse of the disclosed compounds of the invention is in combination withparathyroid hormone, PTH(1-34) or bisphosphonates, such as MK-217(alendronate).

A still further use of the compounds of the invention is in combinationwith estrogen, testosterone, a selective estrogen receptor modulator,such as tamoxifen or raloxifene, or other androgen receptor modulators,such as those disclosed in Edwards, J. P. et al., Bio. Med. Chem. Let.,9, 1003-1008 (1999) and Hamann, L. G. et al., J. Med. Chem., 42, 210-212(1999).

A further use of the compounds of this invention is in combination withprogesterone receptor agonists (“PRA”), such as levonorgestrel,medroxyprogesterone acetate (MPA).

The compounds of the present invention can be employed alone or incombination with each other and/or other modulators of nuclear hormonereceptors or other suitable therapeutic agents useful in the treatmentof the aforementioned disorders including: anti-diabetic agents;anti-osteoporosis agents; anti-obesity agents; anti-inflammatory agents;anti-anxiety agents; anti-depressants; anti-hypertensive agents;anti-platelet agents; anti-thrombotic and thrombolytic agents; cardiacglycosides; cholesterol/lipid lowering agents; mineralocorticoidreceptor antagonists; phosphodiesterase inhibitors; protein tyrosinekinase inhibitors; thyroid mimetics (including thyroid receptoragonists); anabolic agents; HIV or AIDS therapies; therapies useful inthe treatment of Alzheimer's disease and other cognitive disorders;therapies useful in the treatment of sleeping disorders;anti-proliferative agents; and anti-tumor agents.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include biguanides (e.g.,metformin), glucosidase inhibitors (e.g., acarbose), insulins (includinginsulin secretagogues or insulin sensitizers), meglitinides (e.g.,repaglinide), sulfonylureas (e.g., glimepiride, glyburide andglipizide), biguanide/glyburide combinations (e.g., Glucovance®),thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone),PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dualagonists, SGLT2 inhibitors, glycogen phosphorylase inhibitors,inhibitors of fatty acid binding protein (aP2) such as those disclosedin U.S. Ser. No. 09/519,079 filed Mar. 6, 2000, glucagon-like peptide-1(GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate,risedronate, PTH, PTH fragment, raloxifene, calcitonin, steroidal ornon-steroidal progesterone receptor agonists, RANK ligand antagonists,calcium sensing receptor antagonists, TRAP inhibitors, selectiveestrogen receptor modulators (SERM), estrogen and AP-1 inhibitors.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include aP2 inhibitors, such as thosedisclosed in U.S. Ser. No. 09/519,079 filed Mar. 6, 2000, PPAR gammaantagonists, PPAR delta agonists, beta 3 adrenergic agonists, such asAJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) orother known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983 and 5,488,064, a lipase inhibitor, suchas orlistat or ATL-962 (Alizyme), a serotonin (and dopamine) reuptakeinhibitor, such as sibutramine, topiramate (Johnson & Johnson) oraxokine (Regeneron), a thyroid receptor beta drug, such as a thyroidreceptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO 99/00353(KaroBio) and GB98/284425 (KaroBio), and/or an anorectic agent, such asdexamphetamine, phentermine, phenylpropanolamine or mazindol.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include prednisone,dexamethasone, Enbrel®, cyclooxygenase inhibitors (i.e., COX-1 and/orCOX-2 inhibitors such as NSAIDs, aspirin, indomethacin, ibuprofen,piroxicam, Naproxen®, Celebrex®, Vioxx®), CTLA4-Ig agonists/antagonists,CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate(CellCept®) integrin antagonists, alpha-4 beta-7 integrin antagonists,cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, tumornecrosis factor (TNF) antagonists (e.g., infliximab, OR1384),prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493,CD4 antagonists (e.g., priliximab), p38 mitogen-activated protein kinaseinhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors,and therapies for the treatment of irritable bowel syndrome (e.g.,Zelmac® and Maxi-K® openers such as those disclosed in U.S. Pat. No.6,184,231 B1).

Example of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, oxazepam, and hydroxyzine pamoate.

Examples of suitable anti-depressants for use in combination with thecompounds of the present invention include citalopram, fluoxetine,nefazodone, sertraline, and paroxetine.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g. diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), rennin inhibitors, ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazapril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

Examples of suitable anti-platelet agents for use in combination withthe compounds of the present invention include GPIIb/IIIa blockers(e.g., abciximab, eptifibatide, tirofiban), P2Y12 antagonists (e.g.,clopidogrel, ticlopidine, CS-747), thromboxane receptor antagonists(e.g., ifetroban), aspirin, and PDE-III inhibitors (e.g., dipyridamole)with or without aspirin.

Examples of suitable cardiac glycosides for use in combination with thecompounds of the present invention include digitalis and ouabain.

Examples of suitable cholesterol/lipid lowering agents for use incombination with the compounds of the present invention include HMG-CoAreductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin,simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin)and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)),squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACATinhibitors, MTP inhibitors, lipooxygenase inhibitors, cholesterolabsorption inhibitors, and cholesterol ester transfer protein inhibitors(e.g., CP-529414).

Examples of suitable mineralocorticoid receptor antagonists for use incombination with the compounds of the present invention includespironolactone and eplerinone.

Examples of suitable phosphodiesterase inhibitors for use in combinationwith the compounds of the present invention include PDEIII inhibitorssuch as cilostazol, and PDE V inhibitors such as sildenafil.

Examples of suitable thyroid mimetics for use in combination with thecompounds of the present invention include thyrotropin, polythyroid,KB-130015, and dronedarone.

Examples of suitable anabolic agents for use in combination with thecompounds of the present invention include testosterone, TRHdiethylstilbesterol, estrogens, β-agonists, theophylline, anabolicsteroids, dehydroepiandrosterone, enkephalins, E-series prostagladins,retinoic acid and compounds as disclosed in U.S. Pat. No. 3,239,345,e.g., Zeranol®; U.S. Pat. No. 4,036,979, e.g., Sulbenox® or peptides asdisclosed in U.S. Pat. No. 4,411,890.

Examples of suitable HIV or AIDS therapies for use in combination withthe compounds of the present invention include indinavir sulfate,saquinavir, saquinavir mesylate, ritonavir, lamivudine, zidovudine,lamivudine/zidovudine combinations, zalcitabine, didanosine, stavudine,and megestrol acetate.

Examples of suitable therapies for treatment of Alzheimer's disease andcognitive disorders for use in combination with the compounds of thepresent invention include donepezil, tacrine, revastigmine, 5HT6, gammasecretase inhibitors, beta secretase inhibitors, SK channel blockers,Maxi-K blockers, and KCNQs blockers.

Examples of suitable therapies for treatment of sleeping disorders foruse in combination with the compounds of the present invention includemelatonin analogs, melatonin receptor antagonists, ML1B agonists, andGABA/NMDA receptor antagonists.

Examples of suitable anti-proliferative agents for use in combinationwith the compounds of the present invention include cyclosporin A,paclitaxel, FK 506, and adriamycin.

Examples of suitable anti-tumor agents for use in combination with thecompounds of the present invention include paclitaxel, adriamycin,epothilones, cisplatin and carboplatin.

Compounds of the present invention can further be used in combinationwith nutritional supplements such as those described in U.S. Pat. No.5,179,080, especially in combination with whey protein or casin, aminoacids (such as leucine, branched amino acids and hydroxymethylbutyrate),triglycerides, vitamins (e.g., A, B6, B12, folate, C, D and E), minerals(e.g., selenium, magnesium, zinc, chromium, calcium and potassium),carnitine, lipoic acid, creatine, and coenzyme Q-10.

In addition, compounds of the present invention can be used incombination with therapeutic agents used in the treatment of sexualdysfunction, including but not limited to PDE5 inhibitors, such assildenafil or IC-351; with an antiresorptive agent, hormone replacementtherapies, vitamin D analogues, calcitonins, elemental calcium andcalcium supplements, cathepsin K inhibitors, MMP inhibitors, vitronectinreceptor antagonists, Src SH₂ antagonists, vacular —H⁺-ATPaseinhibitors, progesterone receptor agonists, ipriflavone, fluoride, RANKantagonists, PTH and its analogues and fragments, Tibolone, HMG-CoAreductase inhibitors, SERM's, p38 inhibitors, prostanoids, 17-betahydroxysteroid dehydrogenase inhibitors and Src kinase inhibitors.

Compounds of the present invention can be used in combination with malecontraceptives, such as nonoxynol 9 or therapeutic agents for thetreatment of hair loss, such as minoxidil and finasteride orchemotherapeutic agents, such as with LHRH agonists.

For their preferred anticancer or antiangiogenic use, the compounds ofthe present invention can be administered either alone or in combinationwith other anti-cancer and cytotoxic agents and treatments useful in thetreatment of cancer or other proliferative diseases, for example, wherethe second drug has the same or different mechanism of action than thepresent compounds of formula I. Examples of classes of anti-cancer andcytotoxic agents useful in combination with the present compoundsinclude but are not limited to: alkylating agents such as nitrogenmustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes;EGFR inhibitors such as small molecule EGFR inhibitors, EGFR antibodiessuch as C225 (Erbitux); antimetabolites such as folate antagonists,purine analogues, and pyrimidine analogues; antibiotics such asanthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin;enzymes such as L-asparaginase; farnesyl-protein transferase inhibitors;5α reductase inhibitors; inhibitors of 17β-hydroxy steroid dehydrogenasetype 3 or type 1; hormonal agents such as glucocorticoids,estrogens/antiestrogens, androgens/antiandrogens, progestins, andluteinizing hormone-releasing hormone antagonists, octreotide acetate;microtubule-disruptor agents, such as ecteinascidins or their analogsand derivatives; microtubule-stabilizing agents such as taxanes, forexample, paclitaxel (Taxol®), docetaxel (Taxotere®), and their analogs,and epothilones, such as epothilones A-F and their analogs;plant-derived products, such as vinca alkaloids, epipodophyllotoxins,taxanes; and topiosomerase inhibitors; prenyl-protein transferaseinhibitors; and miscellaneous agents such as hydroxyurea, procarbazine,mitotane, hexamethylmelamine, platinum coordination complexes such ascisplatin and carboplatin; and other agents used as anti-cancer andcytotoxic agents such as biological response modifiers, growth factors;immune modulators and monoclonal antibodies. The compounds of theinvention may also be used in conjunction with radiation therapy.

Representative examples of these classes of anti-cancer and cytotoxicagents include but are not limited to mechlorethamine hydrochloride,cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan,carmustin, lomustine, semustine, streptozocin, thiotepa, dacarbazine,methotrexate, thioguanine, mercaptopurine, fludarabine, pentastatin,cladribin, cytarabine, fluorouracil, doxorubicin hydrochloride,daunorubicin, idarubicin, bleomycin sulfate, mitomycin C, actinomycin D,safracins, saframycins, quinocarcins, discodermolides, vincristine,vinblastine, vinorelbine tartrate, etoposide, etoposide phosphate,teniposide, paclitaxel, tamoxifen, estramustine, estramustine phosphatesodium, flutamide, buserelin, leuprolide, pteridines, diyneses,levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim,sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride,betamethosone, gemcitabine hydrochloride, altretamine, and topoteca andany analogs or derivatives thereof.

Preferred member of these classes include, but are not limited to,paclitaxel, cisplatin, carboplatin, doxorubicin, caminomycin,daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C,ecteinascidin 743, or porfiromycin, 5-fluorouracil, 6-mercaptopurine,gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxinderivatives such as etoposide, etoposide phosphate or teniposide,melphalan, vinblastine, vincristine, leurosidine, vindesine andleurosine.

Examples of anticancer and other cytotoxic agents include the following:epothilone derivatives as found in German Patent No. 4138042.8; WO97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO99/65913, WO 99/67252, WO 99/67253 and WO 00/00485; cyclin dependentkinase inhibitors as found in WO 99/24416 (see also U.S. Pat. No.6,040,321); and prenyl-protein transferase inhibitors as found in WO97/30992 and WO 98/54966; and agents such as those described genericallyand specifically in U.S. Pat. No. 6,011,029 (the compounds of which U.S.patent can be employed together with any NHR modulators (including, butnot limited to, those of present invention) such as AR modulators, ERmodulators, with LHRH modulators, or with surgical castration,especially in the treatment of cancer).

The combinations of the present invention can also be formulated orco-administered with other therapeutic agents that are selected fortheir particular usefulness in administering therapies associated withthe aforementioned conditions. For example, the compounds of theinvention may be formulated with agents to prevent nausea,hypersensitivity and gastric irritation, such as antiemetics, and H₁ andH₂ antihistaminics.

As it pertains to the treatment of cancer, the compounds of thisinvention are most preferably used alone or in combination withanti-cancer treatments such as radiation therapy and/or with cytostaticand/or cytotoxic agents, such as, but not limited to, DNA interactiveagents, such as cisplatin or doxorubicin; inhibitors of farnesyl proteintransferase, such as those described in U.S. Pat. No. 6,011,029;topoisomerase II inhibitors, such as etoposide; topoisomerase Iinhibitors, such as CPT-11 or topotecan; tubulin stabilizing agents,such as paclitaxel, docetaxel, other taxanes, or epothilones; hormonalagents, such as tamoxifen; thymidilate synthase inhibitors, such as5-fluorouracil; antimetabolites, such as methoxtrexate; antiangiogenicagents, such as angiostatin, ZD6474, ZD6126 and comberstatin A2; kinaseinhibitors, such as her2 specific antibodies, Iressa and CDK inhibitors;histone deacetylase inhibitors, such as CI-994 and MS-27-275. Suchcompounds may also be combined with agents which suppress the productionof circulating testosterone such as LHRH agonists or antagonists or withsurgical castration. Exemplary combination therapies (e.g., for thetreatment of prostate cancer) for use with a compound of the presentinvention include an LHRH modulator or prednisone.

The present invention also contemplates kits, for example, for thetreatment of prostate cancer, comprising a first container (such as avial) containing a pharmaceutical formulation comprising a compound ofthe present invention, said compound optionally in a pharmaceuticallyacceptable carrier, and a second container (such as a vial) containing apharmaceutical formulation comprising one or more agents (such as anLHRH modulator) to be used in combination with said compound of thepresent invention, said agent(s) optionally in a pharmaceuticallyacceptable carrier.

For example, known therapies for advanced metastatic prostate cancerinclude “complete androgen ablation therapy” wherein tumor growth isinhibited by controlling the supply of androgen to the prostate tissuesvia chemical castration (castration serves to inhibit the production ofcirculating testosterone (T) and dihydrotestosterone (DHT)) followed bythe administration of androgen receptor (AR) antagonists (which inhibitthe function T/DHT derived from the conversion of circulating androgenprecursors to T/DHT by the prostate tissue). The compounds of thepresent invention can be employed as AR antagonists in complete ablationtherapy, alone or in combination with other AR antagonists such asFlutamide, Casodex, Nilutamide, or Cyproterone acetate.

The present invention provides compounds which can be used to treatpatients suffering from prostate cancer resistant to androgen receptorantagonists which are not within formula I of the invention (or saltsthereof), such as bicalutamide. The invention thus further contemplatesa method of treating prostate cancer resistant to an androgen receptorantagonist other than those of formula I or salts thereof, comprisingthe step of administering to a patient in need thereof a compoundcapable of reducing the growth rate of the tumor mass of said cancer inan amount effective therefor. The term “reducing the growth rate of saidtumor mass” denotes reduction in the growth rate (including, of course,stabilization or reduction in size) of said tumor mass upon treatmentrelative to the growth rate upon treatment with said androgen receptorantagonist other than those of formula I or salts thereof. Compounds ofthe formula I and pharmaceutically acceptable salts thereof of thepresent invention are preferred such compounds.

The present invention also contemplates use of an antiestrogen and/oraromatase inhibitor in combination with a compound of the presentinvention, for example, to assist in mitigating side effects associatedwith antiandrogen therapy such as gynecomastia. Exemplary antiestrogenand/or aromatase inhibitors include anastrozole (Arimidex), tamoxifencitrate (Nolvadex), exemestane (Aromasin), toremifene citrate(Fareston), letrozole (Femara), raloxifene hydrochloride (Evista),Faslodex, or 923 (Wyeth Ayerst).

The compounds of the present invention may be employed adjuvant tosurgery.

Another application of the present compounds is in combination withantibody therapy such as but not limited to antibody therapy againstPSCA. An additional application is in concert with vaccine/immunemodulating agents for the treatment of cancer.

Compounds of the present invention can be employed in accordance withthe methods described in U.S. Provisional Patent Application Ser. No.60/284,438, entitled “Selective Androgen Receptor Modulators and Methodsfor Their Identification, Design and Use” filed Apr. 18, 2001 by Mark E.Salvati et al., which Provisional Patent Application is incorporatedherein by reference in its entirety (including, but not limited to,reference to all specific compounds within formula I of the presentinvention), and U.S. patent application Ser. No. 09/885,827, entitled“Selective Androgen Receptor Modulators and Methods for TheirIdentification, Design and Use” filed Jun. 20, 2001 by Mark E. Salvatiet al., which patent application is incorporated herein by reference inits entirety (including, but not limited to, reference to all specificcompounds within formula I of the present invention).

For racemates of compounds of the present invention, one enantiomer can,for example be a full AR antagonist while the other can be an ARantagonist in tumor tissue while having no activity or agonist activityin nontumor tissue containing the androgen receptor.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, can be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The following assays can be employed in ascertaining the activity of acompound as a NHR modulator. Preferred are those compounds with anactivity greater than 20 μm for binding or transactivation in any ofthese assays. Various compounds of the present invention were determinedto have AR modulator activity utilizing the transactivation assay, andstandard AR binding assays as described following.

Transactivation Assays:

AR Specific Assay:

Compounds of the present invention were tested in transactivation assaysof a transfected reporter construct and using the endogenous androgenreceptor of the host cells. The transactivation assay provides a methodfor identifying functional agonists and partial agonists that mimic, orantagonists that inhibit, the effect of native hormones, in this case,dihydrotestosterone (DHT). This assay can be used to predict in vivoactivity as there is a good correlation in both series of data. See,e.g. T. Berger et al., J. Steroid Biochem. Molec. Biol. 773 (1992), thedisclosure of which is herein incorporated by reference.

For the transactivation assay a reporter plasmid is introduced bytransfection (a procedure to induce cells to take foreign genes) intothe respective cells. This reporter plasmid, comprising the cDNA for areporter protein, such as secreted alkaline phosphatase (SEAP),controlled by prostate specific antigen (PSA) upstream sequencescontaining androgen response elements (AREs). This reporter plasmidfunctions as a reporter for the transcription-modulating activity of theAR. Thus, the reporter acts as a surrogate for the products (mRNA thenprotein) normally expressed by a gene under control of the AR and itsnative hormone. In order to detect antagonists, the transactivationassay is carried out in the presence of constant concentration of thenatural AR hormone (DHT) known to induce a defined reporter signal.Increasing concentrations of a suspected antagonist will decrease thereporter signal (e.g., SEAP production). On the other hand, exposing thetransfected cells to increasing concentrations of a suspected agonistwill increase the production of the reporter signal.

For this assay, LNCaP and MDA 453 cells were obtained from the AmericanType Culture Collection (Rockville, Md.), and maintained in RPMI 1640 orDMEM medium supplemented with 10% fetal bovine serum (FBS; Gibco)respectively. The respective cells were transiently transfected byelectroporation according to the optimized procedure described byHeiser, 130 Methods Mol. Biol., 117 (2000), with thepSEAP2/PSA540/Enhancer reporter plasmid. The reporter plasmid, wasconstructed as follows: commercial human placental genomic DNA was usedto generate by Polymerase Cycle Reaction (PCR) a fragment containing theBglII site (position 5284) and the Hind III site at position 5831 of thehuman prostate specific antigen promoter (Accession # U37672), Schuur,et al., J. Biol. Chem., 271 (12): 7043-51 (1996). This fragment wassubcloned into the pSEAP2/basic (Clontech) previously digested withBglII and HindIII to generate the pSEAP2/PSA540 construct. Then afragment bearing the fragment of human PSA upstream sequence betweenpositions −5322 and −3873 was amplified by PCR from human placentalgenomic DNA. A XhoI and a BglII sites were introduced with the primers.The resulting fragment was subcloned into pSEAP2/PSA540 digested withXhoI and BglII respectively, to generate the pSEAP2/PSA540/Enhancerconstruct. LNCaP and MDA 453 cells were collected in media containing10% charcoal stripped FBS. Each cell suspension was distributed into twoGene Pulser Cuvetts (Bio-Rad) which then received 8 μg of the reporterconstruct, and electoporated using a Bio-Rad Gene Pulser at 210 voltsand 960 μFaraday. Following the transfections the cells were washed andincubated with media containing charcoal stripped fetal bovine serum inthe absence (blank) or presence (control) of 1 nM dihydrotestosterone(DHT; Sigma Chemical) and in the presence or absence of the standardanti-androgen bicalutamide or compounds of the present invention inconcentrations ranging from 10-10 to 10-5 M (sample). Duplicates wereused for each sample. The compound dilutions were performed on a Biomek2000 laboratory workstation.

After 48 hours, a fraction of the supernatant was assayed for SEAPactivity using the Phospha-Light Chemiluminescent Reporter Gene AssaySystem (Tropix, Inc). Viability of the remaining cells was determinedusing the CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay(MTS Assay, Promega). Briefly, a mix of a tetrazolium compound(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt; MTS) and an electron coupling reagent (phenazinemethosulfate; PMS) are added to the cells. MTS (Owen's reagent) isbioreduced by cells into a formazan that is soluble in tissue culturemedium, and therefore its absorbance at 490 nm can be measured directlyfrom 96 well assay plates without additional processing. The quantity offormazan product as measured by the amount of 490 nm absorbance isdirectly proportional to the number of living cells in culture. For eachreplicate the SEAP reading was normalized by the Abs490 value derivedfrom the MTS assay. For the antagonist mode, the % Inhibition wascalculated as:% Inhibition=100×(1−[average control−average blank/averagesample−average blank])Data was plotted and the concentration of compound that inhibited 50% ofthe normalized SEAP was quantified (IC₅₀).

For the agonist mode % Control was referred as the effect of the testedcompound compared to the maximal effect observed with the naturalhormone, in this case DHT, and was calculated as:% Control=100×average sample−average blank/average control−average blankData was plotted and the concentration of compound that activates tolevels 50% of the normalized SEAP for the control was quantified (EC₅₀).

GR Specificity Assay:

The reporter plasmid utilized was comprised of the cDNA for the reporterSEAP protein, as described for the AR specific transactivation assay.Expression of the reporter SEAP protein was controlled by the mousemammary tumor virus long terminal repeat (MMTV LTR) sequences thatcontains three hormone response elements (HREs) that can be regulated byboth GR and PR see, e.g. G. Chalepakis et al., Cell, 53(3), 371 (1988).This plasmid was transfected into A549 cells, which expresses endogenousGR, to obtain a GR specific transactivation assay. A549 cells wereobtained from the American Type Culture Collection (Rockville, Md.), andmaintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS;Gibco). Determination of the GR specific antagonist activity of thecompounds of the present invention was identical to that described forthe AR specific transactivation assay, except that the DHT was replacedwith 5 nM dexamethasone (Sigma Chemicals), a specific agonist for GR.Determination of the GR specific agonist activity of the compounds ofthe present invention was performed as described for the ARtransactivation assay, wherein one measures the activation of the GRspecific reporter system by the addition of a test compound, in theabsence of a known GR specific agonists ligand.

PR Specific Assay:

The reporter plasmid utilized was comprised of the cDNA for the reporterSEAP protein, as described for the AR specific transactivation assay.Expression of the reporter SEAP protein was controlled by the mousemammary tumor virus long terminal repeat (MMTV LTR) sequences thatcontains three hormone response elements (HREs) that can be regulated byboth GR and PR. This plasmid was transfected into T47D, which expressesendogenous PR, to obtain a PR specific transactivation assay. T47D cellswere obtained from the American Type Culture Collection (Rockville,Md.), and maintained in DMEM medium supplemented with 10% fetal bovineserum (FBS; Gibco). Determination of the PR specific antagonist activityof the compounds of the present invention was identical to thatdescribed for the AR specific transactivation assay, except that the DHTwas replaced with 1 nM Promegastone (NEN), a specific agonist for PR.Determination of the PR specific agonist activity of the compounds ofthe present invention was performed as described for the ARtransactivation assay, wherein one measures the activation of the PRspecific reporter system by the addition of a test compound, in theabsence of a known PR specific agonists ligand.

AR Binding Assay:

For the whole cell binding assay, human LNCaP cells (T877A mutant AR) orMDA 453 (wild type AR) in 96-well microtiter plates containing RPMI 1640or DMEM supplemented with 10% charcoal stripped CA-FBS (CocalecoBiologicals) respectively, were incubated at 37° C. to remove anyendogenous ligand that might be complexed with the receptor in thecells. After 48 hours, either a saturation analysis to determine theK_(d) for tritiated dihydrotestosterone, [³H]-DHT, or a competitivebinding assay to evaluate the ability of test compounds to compete with[³H]-DHT were performed. For the saturation analysis, media (RPMI 1640or DMEM-0.2% CA-FBS) containing [³H]-DHT (in concentrations ranging from0.11 nM to 16 nM) in the absence (total binding) or presence(non-specific binding) of a 500-fold molar excess of unlabeled DHT wereadded to the cells. After 4 hours at 37° C., an aliquot of the totalbinding media at each concentration of [³H]-DHT was removed to estimatethe amount of free [³H]-DHT. The remaining media was removed, cells werewashed three times with PBS and harvested onto UniFilter GF/B plates(Packard), Microscint (Packard) was added and plates counted in aTop-Counter (Packard) to evaluate the amount of bound [³H]-DHT.

For the saturation analysis, the difference between the total bindingand the non-specific binding, was defined as specific binding. Thespecific binding was evaluated by Scatchard analysis to determine theK_(d) for [³H]-DHT. See e.g. D. Rodbard, Mathematics and statistics ofligand assays: an illustrated guide: In: J. Langon and J. J. Clapp,eds., Ligand Assay, Masson Publishing U.S.A., Inc., New York, pp. 45-99,(1981), the disclosure of which is herein incorporated by reference.

For the competition studies, media containing 1 nM [³H]-DHT andcompounds of the invention (“test compounds”) in concentrations rangingfrom 10⁻¹⁰ to 10⁻⁵ M were added to the cells. Two replicates were usedfor each sample. After 4 hours at 37° C., cells were washed, harvestedand counted as described above. The data was plotted as the amount of[³H]-DHT (% of control in the absence of test compound) remaining overthe range of the dose response curve for a given compound. Theconcentration of test compound that inhibited 50% of the amount of[³H]-DHT bound in the absence of competing ligand was quantified (IC₅₀)after log-logit transformation. The K_(I) values were determined byapplication of the Cheng-Prusoff equation to the IC₅₀ values, where:

$K_{t} = {\frac{{IC}_{50}}{\left( {1 + {{\left( {}^{3}{H\text{-}{DHT}} \right)/K_{d}}\mspace{14mu}{for}\mspace{14mu}{\,^{3}H}\text{-}{DHT}}} \right)}.}$After correcting for non-specific binding, IC₅₀ values were determined.The IC₅₀ is defined as the concentration of competing ligand needed toreduce specific binding by 50%. The K_(d)s for [³H]-DHT for MDA 453 andLNCaP were 0.7 and 0.2 nM respectively.Human Prostate Cell Proliferation Assay:

Compounds of the present invention were tested (“test compounds”) on theproliferation of human prostate cancer cell lines. For that, MDA PCa2bcells, a cell line derived from the metastasis of a patient that failedcastration, Navone et al., Clin. Cancer Res., 3, 2493-500 (1997), wereincubated with or without the test compounds for 72 hours and the amountof [³H]-thymidine incorporated into DNA was quantified as a way toassess number of cells and therefore proliferation. The MDA PCa2b cellline was maintained in BRFF-HPC1 media (Biological Research Faculty &Facility Inc., MD) supplemented with 10% FBS. For the assay, cells wereplated in Biocoated 96-well microplates and incubated at 37° C. in 10%FBS (charcoal-stripped)/BRFF-BMZERO (without androgens). After 24 hours,the cells were treated in the absence (blank) or presence of 1 nM DHT(control) or with test compounds (sample) of the present invention inconcentrations ranging from 10⁻¹ to 10⁻⁵ M. Duplicates were used foreach sample. The compound dilutions were performed on a Biomek 2000laboratory work station. Seventy two hours later 0.44 uCi. of[³H]-Thymidine (Amersham) was added per well and incubated for another24 h followed by tripsinization, harvesting of the cells onto GF/Bfilters. Micro-scint PS were added to the filters before counting themon a Beckman TopCount.

The % Inhibition was calculated as:%Inhibition=100×(1−[average_(control)−average_(blank)/average_(sample)−average_(blank)])Data was plotted and the concentration of compound that inhibited 50% ofthe [³H]-Thymidine incorporation was quantified (IC₅₀).C2C12 Mouse Mvoblast Transactivation Assay:

Two functional transactivation assays were developed to assess theefficacy of androgen agonists in a muscle cell background using aluciferase reporter. The first assay (ARTA Stable 1) uses a cell line,Stable 1 (clone #72), which stably expresses the full length ratandrogen receptor but requires the transient transfection of anenhancer/reporter. This cell line was derived from C2C12 mouse moyoblastcells. The second assay (ARTA Stable 2) uses a cell line, Stable 2(clone #133), derived from Stable 1 which stably expresses both rAR andthe enhancer/luciferase reporter.

The enhancer/reporter construct used in this system ispGL3/2XDR-1/luciferase. 2×DR-1 was reported to be an AR specificresponse element in CV-1 cells, Brown et. al. The Journal of BiologicalChemisty 272, 8227-8235, (1997). It was developed by random mutagenesisof an AR/GR consensus enhancer sequence.

ARTA Stable 1:

-   1. Stable 1 cells are plated in 96 well format at 6,000 cells/well    in high glucose DMEM without phenol red (Gibco BRL, Cat. No.:    21063-029) containing 10% charcoal and dextran treated FBS (HyClone    Cat. No.: SH30068.02), 50 mM HEPES Buffer (Gibco BRL, Cat. No.:    15630-080), 1×MEM Na Pyruvate (Gibco BRL, Cat. No.: 11360-070), 0.5×    Antibiotic-Antimycotic, and 800 μg/ml Geneticin (Gibco BRL, Cat.    No.: 10131-035).-   2. 48 hours later, cells are transfected with pGL3/2XDR-1/luciferase    using LipofectAMINE Plus™ Reagent (Gibco BRL, Cat. No.: 10964-013).    Specifically, 5 ng/well pGL3/2XDR-1/luciferase DNA and 50 ng/well    Salmon Sperm DNA (as carrier) are diluted with 5 μl/well Opti-MEMem    media (Gibco BRL, Cat. No.: 31985-070). To this, 0.5 μl/well Plus    reagent is added. This mixture is incubated for 15 minutes at room    temperature. In a separate vessel, 0.385 μl/well LipofectAMINE    reagent is diluted with 5 μl/well Opti-MEM. The DNA mixture is then    combined with the LipofectAMINE mixture and incubated for an    additional 15 minutes at room temperature. During this time, the    media from the cells is removed and replaced with 60 μl/well of    Opti-MEM. To this is added 10 μl/well of the DNA/LipofectAMINE    transfection mixture. The cells are incubated for 4 hours.-   3. The transfection mixture is removed from the cells and replaced    with 90 μl of media as in #1 above.-   4. 10 μl/well of appropriate drug dilution is placed in each well.-   5. 24 hours later, the Steady-Glo™ Luciferase Assay System is used    to detect activity according to the manufacturer's instructions    (Promega, Cat. No.: E2520).

ARTA Stable 2

-   1. Stable 2 cells are plated in 96 well format at 6,000 cells/well    in high glucose DMEM without phenol red (Gibco BRL, Cat. No.:    21063-029) containing 10% charcoal and dextran treated FBS (HyClone    Cat. No.: SH30068.02), 50 mM HEPES Buffer (Gibco BRL, Cat. No.:    15630-080), 1×MEM Na Pyruvate (Gibco BRL, Cat. No.: 11360-070), 0.5×    Antibiotic-Antimycotic, 800 μg/ml Geneticin (Gibco BRL, Cat. No.:    10131-035) and 800 μg/ml Hygromycin β (Gibco BRL, Cat. No.:    10687-010).-   2. 48 hours later, the media on the cells is removed and replaced    with 90 μl fresh. 10 μl/well of appropriate drug dilution is placed    in each well.-   3. 24 hours later, the Steady-Glo™ Luciferase Assay System is used    to detect activity according to the manufacturer's instructions    (Promega, Cat. No.: E2520).    See U.S. patent application Ser. No. 09/885,831, entitled “Cell    Lines and Cell-BasedAssays for Identification of Androgen Receptor    Modulators” filed Jun. 20, 2001 by Jacek Ostrowski et al., which    patent application is incorporated herein by reference in its    entirety.    Proliferation Assays    Murine Breast Cell Proliferation Assay:

The ability of compounds of the present invention (“test compounds”) tomodulate the function of the AR was determined by testing said compoundsin a proliferation assay using the androgen responsive murine breastcell line derived from the Shionogi tumor, Hiraoka et al., Cancer Res.,47, 6560-6564 (1987). Stable AR dependent clones of the parentalShionogi line were established by passing tumor fragments under thegeneral procedures originally described in Tetuo, et. al., CancerResearch 25, 1168-1175 (1965). From the above procedure, one stableline, SC114, was isolated, characterized and utilized for the testing ofexample compounds. SC114 cells were incubated with or without the testcompounds for 72 hours and the amount of [3H]-thymidine incorporatedinto DNA was quantified as a surrogate endpoint to assess the number ofcells and therefore the proliferation rate as described in Suzuki et.al., J. Steroid Biochem. Mol. Biol. 37, 559-567 (1990). The SC114 cellline was maintained in MEM containing 10⁻⁸ M testosterone and 2%DCC-treated FCS. For the assay, cells were plated in 96-well microplatesin the maintenance media and incubated at 37° C. On the following day,the medium was changed to serum free medium [Ham's F-12:MEM (1:1, v/v)containing 0.1% BSA] with (antagonist mode) or without (agonist mode)10⁻⁸ M testosterone and the test compounds of the present invention inconcentrations ranging from 10⁻¹⁰ to 10⁻⁵ M. Duplicates were used foreach sample. The compound dilutions were performed on a Biomek 2000laboratory work station. Seventy two hours later 0.44uCi of[3H]-Thymidine (Amersham) was added per well and incubated for another 2hr followed by tripsinization, and harvesting of the cells onto GF/Bfilters. Micro-scint PS were added to the filters before counting themon a Beckman TopCount.

For the antagonist mode, the % Inhibition was calculated as:%Inhibition=100×(1−[average_(sample)−average_(blank)/average_(control)−average_(blank)])Data was plotted and the concentration of compound that inhibited 50% ofthe [³H]-Thymidine incorporation was quantified (IC₅₀).

For the agonist mode % Control was referred as the effect of the testedcompound compared to the maximal effect observed with the naturalhormone, in this case DHT, and was calculated as:%Control=100×(average_(sample)−average_(blank))/(average_(control)−average_(blank))Data was plotted and the concentration of compound that inhibited 50% ofthe [³H]-Thymidine incorporation was quantified (EC₅₀).In Vitro Assay to Measure GR Induced AP-1 Transrepression:

The AP-1 assay is a cell based luciferase reporter assay. A549 cells,which contain endogenous glucocorticoid receptor, were stablytransfected with an AP-1 DNA binding site attached to the luciferasegene. Cells are then grown in RPMI+10% fetal calf serum(charcoal-treated)+Penicillin/Streptomycin with 0.5 mg/ml geneticin.Cells are plated the day before the assay at approximately 40000cells/well. On assay day, the media is removed by aspiration and 20 μlassay buffer (RPMI without phenol red+10%-FCS(charcoal-treated)+Pen/Strep) is added to each well. At this pointeither 20 μl assay buffer (control experiments), the compounds of thepresent invention (“test compounds”) (dissolved in DMSO and added atvarying concentrations) or dexamethasome (100 nM in DMSO, positivecontrol) are added to each well. The plates are then pre-incubated for15 minutes at 37° C., followed by stimulation of the cells with 10 ng/mlPMA. The plates are then incubated for 7 hrs at 37° C. after which 40 μlluciferase substrate reagent is added to each well. Activity is measuredby analysis in a luminometer as compared to control experiments treatedwith buffer or dexamethasome. Activity is designated as % inhibition ofthe reporter system as compared to the buffer control with 10 ng/ml PMAalone. The control, dexamethasone, at a concentration of ≦10 μMtypically suppresses activity by 65%. Test compounds which demonstratean inhibition of PMA induction of 50% or greater at a concentration oftest compound of ≦10 μM are deemed active.

Wet Prostate Weight Assay AR Antagonist Assay:

The activity of compounds of the present invention as AR antagonists wasinvestigated in an immature male rat model, a standard, recognized testof antiandrogen activity of a given compound, as described in L. G.Hershberger et al., Proc. Soc. Expt. Biol. Med., 83, 175 (1953); P. C.Walsh and R. F. Gittes, “Inhibition of extratesticular stimuli toprostate growth in the castrated rat by antiandrogens”, Endocrinology,86, 624 (1970); and B. J. Furr et al., “ICI 176,334: A novelnon-steroid, peripherally selective antiandrogen”, J. Endocrinol., 113,R7-9 (1987), the disclosures of which are herein incorporated byreference.

The basis of this assay is the fact that male sexual accessory organs,such as the prostate and seminal vesicles, play an important role inreproductive function. These glands are stimulated to grow and aremaintained in size and secretory function by the continued presence ofserum testosterone (T), which is the major serum androgen (>95%)produced by the Leydig cells in the testis under the control of thepituitary luteinizing hormone (LH) and follicle stimulating hormone(FSH). Testosterone is converted to the more active form,dihydrotestosterone, (DHT), within the prostate by 5α-reductase. Adrenalandrogens also contribute about 20% of total DHT in the rat prostate,compared to 40% of that in 65-year-old men. F. Labrie et al. Clin.Invest. Med., 16, 475-492 (1993). However, this is not a major pathway,since in both animals and humans, castration leads to almost completeinvolution of the prostate and seminal vesicles without concomitantadrenalectomy. Therefore, under normal conditions, the adrenals do notsupport significant growth of prostate tissues. M. C. Luke and D. S.Coffey, “The Physiology of Reproduction” ed. By E. Knobil and J. D.Neill, 1, 1435-1487 (1994). Since the male sex organs are the tissuesmost responsive to modulation of the androgen activity, this model isused to determine the androgen dependent growth of the sex accessoryorgans in immature castrated rats.

Male immature rats (19-20 days old Sprague-Dawley, HarlanSprague-Dawely) were castrated under metofane ansestesia. Five daysafter surgery these castrated rats (60-70 g, 23-25 day-old) were dosedfor 3 days. Animals were dosed sub-cutaneously (s.c.) 1 mg/kg withTestosterone Proprionate (TP) in arachis oil vehicle and anti-androgentest compounds (compounds of the present invention) were dosed orally bygavage (p.o.) in dissolved/suspensions of 80% PEG 400 and 20% Tween 80(PEGTW). Animals were dosed (v/w) at 0.5 ml of vehicle/100 g bodyweight. Experimental groups were as follows:

-   -   1. Control vehicle    -   2. Testosterone Propionate (TP) (3 mg/rat/day, subcutaneous)    -   3. TP plus Casodex (administered p.o. in PEGTW, QD), a        recognized antiandrogen, as a reference compound.    -   4. To demonstrate antagonist activity, a compound of the present        invention (“test compound”) was administered (p.o. in PEGTW, QD)        with TP (s.c. as administered in group 2) in a range of doses.    -   5. To demonstrate agonist activity a compound of the present        invention (“test compound”) was administered alone (p.o. in        PEGTW, QD) in a range of doses.

At the end of the 3-day treatment, the animals were sacrificed, and theventral prostate weighed. To compare data from different experiments,the sexual organs weights were first standardized as mg per 100 g ofbody weight, and the increase in organ weight induced by TP wasconsidered as the maximum increase (100%). ANOVA followed by one-tailedStudent or Fischer's exact test was used for statistical analysis.

The gain and loss of sexual organ weight reflect the changes of the cellnumber (DNA content) and cell mass (protein content), depending upon theserum androgen concentration. See Y. Okuda et al., J. Urol., 145,188-191 (1991), the disclosure of which is herein incorporated byreference. Therefore, measurement of organ wet weight is sufficient toindicate the bioactivity of androgens and androgen antagonist. Inimmature castrated rats, replacement of exogenous androgens increasesseminal vesicles (SV) and the ventral prostate (VP) in a dose dependentmanner.

The maximum increase in organ weight was 4 to 5-fold when dosing 3mg/rat/day of testosterone (T) or 1 mg/rat/day of testosteronepropionate (TP) for 3 days. The EC₅₀ of T and TP were about 1 mg and0.03 mg, respectively. The increase in the weight of the VP and SV alsocorrelated with the increase in the serum T and DHT concentration.Although administration of T showed 5-times higher serum concentrationsof T and DHT at 2 hours after subcutaneous injection than that of TP,thereafter, these high levels declined very rapidly. In contrast, theserum concentrations of T and DHT in TP-treated animals were fairlyconsistent during the 24 hours, and therefore, TP showed about10-30-fold higher potency than free T.

In this immature castrated rat model, a known AR antagonist (Casodex)was also administered simultaneously with 0.1 mg of TP (ED₈₀),inhibiting the testosterone-mediated increase in the weights of the VPand SV in a dose dependent manner. The antagonist effects were similarwhen dosing orally or subcutaneously. Compounds of the invention alsoexhibited AR antagonist activity by suppressing thetestosterone-mediated increase in the weights of VP and SV.

Levator Ani & Wet Prostate Weight Assay AR Agonist Assay:

The activity of compounds of the present invention as AR agonists wasinvestigated in an immature male rat model, a recognized test ofanabolic effects in muscle and sustaining effects in sex organs for agiven compound, as described in L. G. Hershberger et al., Proc. Soc.Expt. Biol. Med., 83, 175 (1953); B. L. Beyler et al, “Methods forevaluating anabolic and catabolic agents in laboratory animals”, J.Amer. Med. Women's Ass., 23, 708 (1968); H. Fukuda et al.,“Investigations of the levator ani muscle as an anabolic steroid assay”,Nago Dai. Yak. Ken. Nem. 14, 84 (1966) the disclosures of which areherein incorporated by reference.

The basis of this assay lies in the well-defined action of androgenicagents on the maintenance and growth of muscle tissues and sexualaccessory organs in animals and man. Androgenic steroids, such astestosterone (T), have been well characterized for their ability tomaintain muscle mass. Treatment of animals or humans after castrationswith an exogenous source of T results in a reversal of muscular atrophy.The effects of T on muscular atrophy in the rat levator ani muscle havebeen well characterized. M. Masuoka et al., “Constant cell population innormal, testosterone deprived and testosterone stimulated levator animuscles” Am. J. Anat. 119, 263 (1966); Z. Gori et al., “Testosteronehypertrophy of levator ani muscle of castrated rats. I. Quantitativedata” Boll.-Soc. Ital. Biol. Sper. 42, 1596 (1966); Z. Gori et al.,“Testosterone hypertrophy of levator ani muscle of castrated rats. II.Electron-microscopic observations” Boll.-Soc. Ital. Biol. Sper. 42, 1600(1966); A. Boris et al., Steroids 15, 61 (1970). As described above, theeffects of androgens on maintenance of male sexual accessory organs,such as the prostate and seminal vesicles, is well described. Castrationresults in rapid involution and atrophy of the prostate and seminalvesicles. This effect can be reversed by exogenous addition ofandrogens. Since both the levator ani muscle and the male sex organs arethe tissues most responsive to the effects of androgenic agents, thismodel is used to determine the androgen dependent reversal of atrophy inthe levator ani muscle and the sex accessory organs in immaturecastrated rats. Sexually mature rats (200-250 g, 6-8 weeks-old,Sprague-Dawley, Harlan) were acquired castrated from the vendor(Taconic). The rats were divided into groups and treated daily for 7 to14 days with one of the following:

-   -   1. Control vehicle    -   2. Testosterone Propionate (TP) (3 mg/rat/day, subcutaneous)    -   3. TP plus Casodex (administered p.o. in PEGTW, QD), a        recognized antiandrogen, as a reference compound.    -   4. To demonstrate antagonist activity, a compound of the present        invention (“test compound”) was administered (p.o. in PEGTW, QD)        with TP (s.c. as administered in group 2) in a range of doses.    -   5. To demonstrate agonist activity a compound of the present        invention (“test compound”) was administered alone (p.o. in        PEGTW, QD) in a range of doses.

At the end of the 7-14-day treatment, the animals were sacrificed bycarbon dioxide, and the levator ani, seminal vesicle and ventralprostate weighed. To compare data from different experiments, thelevator ani muscle and sexual organ weights were first standardized asmg per 100 g of body weight, and the increase in organ weight induced byTP was considered as the maximum increase (100%). Super-anova (onefactor) was used for statistical analysis.

The gain and loss of sexual organ weight reflect the changes of the cellnumber (DNA content) and cell mass (protein content), depending upon theserum androgen concentration. See Y. Okuda et al., J. Urol., 145,188-191 (1991), the disclosure of which is herein incorporated byreference. Therefore, measurement of organ wet weight is sufficient toindicate the bioactivity of androgens and androgen antagonist. Inimmature castrated rats, replacement of exogenous androgens increaseslevator ani, seminal vesicles (SV) and prostate in a dose dependentmanner.

The maximum increase in organ weight was 4 to 5-fold when dosing 3mg/rat/day of testosterone (T) or 1 mg/rat/day of testosteronepropionate (TP) for 3 days. The EC₅₀ of T and TP were about 1 mg and0.03 mg, respectively. The increase in the weight of the VP and SV alsocorrelated with the increase in the serum T and DHT concentration.Although administration of T showed 5-times higher serum concentrationsof T and DHT at 2 hours after subcutaneous injection than that of TP,thereafter, these high levels declined very rapidly. In contrast, theserum concentrations of T and DHT in TP-treated animals were fairlyconsistent during the 24 hours, and therefore, TP showed about10-30-fold higher potency than free T.

MDA PCa2b Human Prostate Zenograft Assay:

In Vivo Antitumor Testing: MDA-PCa-2b human prostate tumors weremaintained in Balb/c nu/nu nude mice. Tumors were propagated assubcutaneous transplants in adult male nude mice (4-6 weeks old) usingtumor fragments obtained from donor mice. Tumor passage occurred every5-6 weeks.

For antitumor efficacy trial, the required number of animals needed todetect a meaningful response were pooled at the start of the experimentand each was given a subcutaneous implant of a tumor fragment (˜50 mg)with a 13-gauge trocar. Tumors were allowed to grow to approx. 100-200mg (tumors outside the range were excluded) and animals were evenlydistributed to various treatment and control groups. Treatment of eachanimal was based on individual body weight. Treated animals were checkeddaily for treatment related toxicity/mortality. Each group of animalswas weighed before the initiation of treatment (Wt1) and then againfollowing the last treatment dose (Wt2). The difference in body weight(Wt2-Wt1) provides a measure of treatment-related toxicity.

Tumor response was determined by measurement of tumors with a calipertwice a week, until the tumors reach a predetermined “target” size of0.5 gm. Tumor weights (mg) were estimated from the formula: Tumorweight=(length×width2)÷2

Tumor response end-point was expressed in terms of tumor growthinhibition (% T/C), defined as the ratio of median tumor weights of thetreated tumors (T) to that of the control group (C).

To estimate tumor cell kill, the tumor volume doubling time was firstcalculated with the formula:TVDT=Median time (days) for control tumors to reach target size−Mediantime (days) for control tumors to reach half the target size sAnd, Log cell kill=(T−C)+(3.32×TVDT)

Statistical evaluations of data were performed using Gehan's generalizedWilcoxon test.

Dunning Prostate Tumor:

Dunning R3327H prostate tumor is a spontaneously derived, welldifferentiated androgen responsive adenocarcinoma of the prostate(Smolev J K, Heston W D, Scott W W, and Coffey D S, Cancer Treat Rep.61, 273-287 (1977)). The growth of the R3327H subline has been selectedfor its highly androgen-dependent and reproducible growth in intact malerats. Therefore, this model and other sublines of this tumor have beenwidely used to evaluate in vivo antitumor activities of antiandrogenssuch as flutamide and bacilutamide/Casodex (Maucher A., and von Angerer,J. Cancer Res. Clin. Oncol., 119, 669-674 (1993), Furr B. J. A. Euro.URL. 18 (suppl. 3), 2-9 (1990), Shain S. A. and Huot R I. J. SteroidBiochem. 31, 711-718 (1988)).

At the beginning of the study, the Dunning tumor pieces (about 4×4 mm)are transplanted subcutaneously to the flank of mature male Copenhagenrats (6-7 weeks old, Harlan-Sprague Dawley, Indianapolis, Md.). About 6weeks after the implantation, the animals with tumors of measurable size(about 80-120 mm²) are randomized into treatment groups (8-10rats/group) and the treatments are initiated. One group of the rats arecastrated to serve as the negative control of tumor growth. Animals aretreated daily with compounds of the current invention, standardantiandrogens such as bacilutamide or vehicle (control) for an averageof 10 to 14 weeks. Test compounds are dissolved in a vehicle of (2.5ml/kg of body weight) 10% polyethylene glycol and 0.05% Tween-80 in 1%carboxymethyl cellulose, PEG/CMC, (Sigma, St Louis, Mo.). Typicaltherapeutic experiments would include three groups of three escalatingdoses for each standard or test compound (in a range of 300-3 mg/kg).

Tumors in the vehicle (control) group reach a size of 1500 to 2500 mm³,whereas the castrated animal group typically shows tumor stasis over the14 weeks of observation. Animals treated orally with 20 mg/kg ofbicalutamide or flutamide would be expected to show a 40% reduction intumor volumes compared to control after 14 weeks of treatment. The sizeof tumors are measured weekly by vernier caliper (Froboz, Switzerland),taking perpendicular measurements of length and width. Tumor volumes aremeasured in mm using the formula: Length×Width×Height=Volume.Statistical differences between treatment groups and control areevaluated using multiple ANOVA analysis followed by one tailnon-parametric Student t test.

Mature Rat Prostate Weight Assay:

The activity of compounds of the present invention were investigated ina mature male rat model, which is a variation of the Levator ani & wetprostate weight assay described above. The above in vivo assays arerecognized assays for determining the anabolic effects in muscle andsustaining effects in sex organs for a given compound, as described inL. G. Hershberger et al., 83 Proc. Soc. Expt. Biol. Med., 175 (1953); B.L. Beyler et al, “Methods for evaluating anabolic and catabolic agentsin laboratory animals”, 23 J. Amer. Med. Women's Ass., 708 (1968); H.Fukuda et al., “Investigations of the levator ani muscle as an anabolicsteroid assay”, 14 Nago Dai. Yak. Ken. Nem. 84 (1966) the disclosures ofwhich are herein incorporated by reference. The basis of this assay liesin the well-defined action of androgenic agents on the maintenance andgrowth of muscle tissues and sexual accessory organs in animals and man.

The male sexual accessory organs, such as the prostate and seminalvesicles, play an important role in reproductive function. These glandsare stimulated to grow and are maintained in size and secretory functionby the continued presence of serum testosterone (T), which is the majorserum androgen (>95%) produced by the Leydig cells in the testis underthe control of the pituitary luteinizing hormone (LH) and folliclestimulating hormone (FSH). Testosterone is converted to the more activeform, dihydrotestosterone, (DHT), within the prostate by 5α-reductase.Adrenal androgens also contribute about 20% of total DHT in the ratprostate, compared to 40% of that in 65-year-old men. F. Labrie et. al.16 Clin. Invest. Med., 475-492 (1993). However, this is not a majorpathway, since in both animals and humans, castration leads to almostcomplete involution of the prostate and seminal vesicles withoutconcomitant adrenalectomy. Therefore, under normal conditions, theadrenals do not support significant growth of prostate tissues, M. C.Luke and D. S. Coffey, “The Physiology of Reproduction” ed. By E. Knobiland J. D. Neill, 1, 1435-1487 (1994). Since the male sex organs and thelevator ani are the tissues most responsive to modulation of theandrogen activity, this model is used to determine the activity ofcompounds that modulate the androgen receptor pathway in mature rats.

Along with its mitogenic activity on tissues such as prostate, seminalvesicle and muscle, testosterone also serves as a negative regulator forits own biosynthesis. Testosterone production in the Leydig cells of thetestis is controlled by the level of circulating LH released from thepituitary gland. LH levels are themselves controlled by the level ofLHRH produced in the hypothalmic region. Testosterone levels in theblood serve to inhibit the secretion of LHRH and subsequently reducelevels of LH and ultimately the levels of circulating testosteronelevels. By measuring blood levels of LH as they are effected bycompounds of the present invention (“test compounds”), it is possible todetermine the level of agonist or antagonist activity of said compoundsat the hypothalamic axis of this endocrine cycle.

Matched sets of Harlan Sprague-Dawely rats (40-42 days old, 180-220 g),were dosed orally by gavage (p.o.) with the test compounds indissolved/suspensions of 80% PEG 400 and 20% Tween 20 (PEGTW) for 14days. Two control groups, one intact and one castrated were dose orallyonly with the PEGTW vehicle. Animals were dosed (v/w) at 0.5 ml ofvehicle/100 g body weight. Experimental groups were as follows:

1. Intact vehicle (p.o., PEGTW, QD)

2. Control vehicle (p.o., PEGTW, QD)

3. Bicalutamide (Casodex, a recognized antiandrogen, as a referencecompound) or a compound of the present invention, p.o. in PEGTW QD. (ina range of doses). At the end of the 14-day treatment, the animals weresacrificed, and the ventral prostate, the seminal vesicles, and thelevator ani were removed surgically and weighed. To compare data fromdifferent experiments, the organs weights were first standardized as mgper 100 g of body weight, and expressed as a percentage of the value ofthe respective organ in the intact group.

Rat luteinizing hormone (rLH) is quantitatively determined with theBiotrak [125 I] kit (Amersham Pharmacia Biotek), following themanufacturer directions. The assay is based on the competition by the LHpresent in the serum of the binding of [¹²⁵I] rLH to an Amerlex-Mbead/antibody suspension. The radioactivity that remains afterincubation with the serum and subsequent washes is extrapolated into astandard curve to obtain a reading in ng/ml.

The gain and loss of sexual organ and levator ani weight reflect thechanges of the cell number (DNA content) and cell mass (proteincontent), depending upon the serum androgen concentration, see Y. Okudaet al., J. Urol., 145, 188-191 (1991), the disclosure of which in hereinincorporated by reference. Therefore, measurement of organ wet weight issufficient to indicate the bioactivity of androgens and androgenantagonist. In the mature rats assay, active agonist agents will have noeffect or will increase the weight of one or more of the androgenresponsive organs (levator ani, prostate, seminal vessicle) and willhave no effect or a suppressive effect on LH secretion. Compounds withantagonist activity will decrease the weight of one or more of theandrogen responsive organs (levator ani, prostate, seminal vesicle) andwill have no effect or a reduced suppressive effect on LH secretion.

CWR22 Human Prostate Zenograft Assay:

In Vivo Antitumor Testing: CWR22 human prostate tumors were maintainedin Balb/c nu/nu nude mice. Tumors were propagated as subcutaneoustransplants in adult male nude mice (4-6 weeks old) using tumorfragments obtained from donor mice. Tumor passage occurred every 5-6weeks.

For antitumor efficacy trial, the required number of animals needed todetect a meaningful response were pooled at the start of the experimentand each was given a subcutaneous implant of a tumor fragment (˜50 mg)with a 13-gauge trocar. Tumors were allowed to grow to approx. 100-200mg (tumors outside the range were excluded) and animals were evenlydistributed to various treatment and control groups. Treatment of eachanimal was based on individual body weight. Treated animals were checkeddaily for treatment related toxicity/mortality. Each group of animalswas weighed before the initiation of treatment (Wt1) and then againfollowing the last treatment dose (Wt2). The difference in body weight(Wt2-Wt1) provides a measure of treatment-related toxicity.

Tumor response was determined by measurement of tumors with a calipertwice a week, until the tumors reach a predetermined “target” size of0.5 gm. Tumor weights (mg) were estimated from the formula: Tumorweight=(length×width2)÷2.

Tumor response end-point was expressed in terms of tumor growthinhibition (% T/C), defined as the ratio of median tumor weights of thetreated tumors (T) to that of the control group (C).

To estimate tumor cell kill, the tumor volume doubling time was firstcalculated with the formula:TVDT=Median time (days) for control tumors to reach target size−Mediantime (days) for control tumors to reach half the target sizeAnd, Log cell kill=(T−C)÷(3.32×TVDT)

Statistical evaluations of data were performed using Gehan's generalizedWilcoxon test.

The following Examples illustrate embodiments of the present invention,and are not intended to limit the scope of the claims. Within certainExamples, one compound of the formula I is prepared and then employed tofurther prepare one or more additional compounds of the formula I orsalts thereof. Methods employed to prepare one compound of the formula Ior salt thereof as described herein can be employed as appropriate toprepare other compounds of the invention.

Abbreviations

The following abbreviations are used herein:

-   -   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene    -   4-DMAP=4-dimethylaminopyridine    -   ee=enantiomeric excess    -   DMF=dimethylformamide    -   EtOAc=ethyl acetate    -   LDA=lithium diisopropylamide    -   Hünig's Base=N,N-diisopropylethylamine    -   Me=methyl    -   RT=retention time    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography    -   TMS=trimethylsilyl    -   pTSA=para-toluenesulfonic acid    -   Δ=heat    -   t-Bu=tert-butyl    -   PhCH₃=toluene    -   Pd/C=palladium on activated charcoal    -   TsCl=tosyl chloride    -   TBSOTf=tert-butyldimethylsilyl trifluoromethane sulfonate    -   TBS=tert-butyldimethylsilane    -   MeI=methyl iodide    -   (BOC)₂O=di-tert-butyl dicarbonate    -   TEA=triethylamine    -   n-BuLi=n-butyllithium    -   rt=room temperature    -   LC=liquid chromatography    -   Ts=tosyl    -   Ph=phenyl    -   EtOH=ethanol    -   DCE=dichloroethane    -   DMSO=dimethylsulfoxide    -   Ra—Ni=Raney Nickel    -   MS=molecular sieves    -   MS(ES)=Electro-Spray Mass Spectrometry    -   mCPBA=m-chloroperoxybenzoic acid    -   sat=saturated    -   AcOH=acetic acid    -   MeOH=methanol    -   Et₂O=diethyl ether    -   Ac=acetyl    -   DEAD=diethyl azodicarboxylate    -   h=hours    -   Et=ethyl    -   WSDCC=water soluble dicarbonyl diimide,        1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    -   TBAF=tetrabutylammonium fluoride    -   DBAD=di-terbutylazodicarboxylate    -   DCC=Dicyclohexylcarbodiimide    -   Wilkinson's catalyst=RhCl(PPh3)3    -   ADDP=1,1-[azodicarbonyl]dipiperidine    -   DMA=dimethylacetamide    -   DME=1,2-dimethoxyethane    -   BOP=benzotriazol-1-yloxytris(dimethylamino)-phosphonium        hexafluorophosphate    -   HRMS=high resolution mass spectrometry    -   TBME=MTBE=methyl tert-butyl ether (i.e.,        2-methoxy-2-methyl-propane)    -   TiCl₂ Cp₂=bis(cyclopentadienyl)titanium dichloride    -   DPPA=diphenylphosphoryl azide    -   HMPA=hexamethylphosphoryl amide    -   V %=volume percent    -   BH₃.MS=borane dimethylsulfate    -   vvm=volume gas per volume liquid per minute

EXAMPLE 1

-   (3aα,4α,7α,7aα)-2-(4-Bromo-3-methylphenyl)tetrahydro-4,7-ethanothiopyrano[3,4-c]pyrrole-1,3,8(2H,4H)-trione    (1C)

A. 4-(tert-Butyldimethylsiloxy)-2H-thiopyran (1A)

2,3-Dihydro-4H-thiopyran-4-one (1.50 g, 13.1 mmol, synthesized asdescribed in Richards et al. J. Org. Chem. 46, 4836-4842 (1981)) wasdissolved in CH₂Cl₂ (130 mL) and triethylamine (5.47 mL, 39.4 mmol) wasadded. tert-Butyldimethylsilyl trifluoromethanesulfonate (3.62 mL, 15.8mmol) was then added. After 10 minutes, the volatiles were removed invacuo at 25° C. The resulting yellow oil was passed through a shortcolumn of SiO₂ eluting with 3% TEA in hexanes to yield 1.82 g (7.97mmol, 61%) of compound 1A as an orange oil.

B. 1-[4-bromo-3-methylphenyl]-1H-pyrrole-2,5-dione (1B)

4-Bromo-3-methylaniline (1.55 g, 8.33 mmol) and maleic anhydride (0.898g, 9.16 mmol) were dissolved in acetic acid (10 mL) and heated at 115°C. for 12 h. The reaction was then cooled to 25° C. and the acetic acidwas removed in vacuo. The resulting residue was suspended in 5% K₂CO₃(100 mL), stirred for 25 minutes, filtered and rinsed with water. Thematerial was then dried in vacuo to give 1.65 g (6.20 mmol, 74%) ofcompound 1B as a light brown solid. HPLC: 100% at 2.96 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).

C. (3aα,4α,7α,7aα)-2-(4-Bromo-3-methylphenyl)tetrahydro-4,7-ethanothiopyrano[3,4-c]pyrrole-1,3,8(2H,4H)-trione(1C)

Compound 1A (0.313 g, 1.41 mmol) and compound 1B (0.250 g, 0.940 mmol)were dissolved in toluene and heated to reflux for 5 h. The toluene wasthen removed by passing a stream of argon through the reaction flask.The residue was then purified by flash chromatography on SiO₂ elutingwith 20% hexane in chloroform. This gave 0.168 g of the enol etherintermediate as a yellow solid. The enol ether intermediate wasdissolved in dichloroethane (2.0 mL) and TFA (0.25 mL) was added. After0.5 h, the reaction was quenched with saturated aqueous NaHCO₃ andextracted with CH₂Cl₂ (2×30 mL). The organics were dried over anhydroussodium sulfate and evaporated to give 0.079 g (0.21 mmol, 22%) ofcompound 1C as a white solid. HPLC: 99% at 3.010 min (retention time)(YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES):m/z 396.9 [M+NH₄]⁺.

EXAMPLE 2(3aα,4α,7α,7aα)-2-(4-Bromo-3-methylphenyl)tetrahydro-4,7-ethanothiopyrano[3,4-c]pyrrole-1,3,8(2H,4H)-trione5,5-dioxide (2)

Compound 1C (0.040 g, 0.11 mmol) was dissolved in CH₂Cl₂ (4.0 mL) andcooled to 0° C. m-CPBA (60% purity, 0.061 g, 0.21 mmol) was added andthe reaction was then warmed to 25° C. After 1 h, a 1:1 mixture ofsaturated NaHCO₃ and saturated sodium sulfite (20 mL) was added withvigorous stirring. After 15 minutes, the mixture was extracted withCH₂Cl₂ (2×30 mL) and the organics were dried over anhydrous sodiumsulfate to yield 0.031 g (0.075 mmol, 71%) of compound 2 as a whitesolid. No purification was necessary. HPLC: 78% at 2.290 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.1% TFA, 41n L/min, monitoring at 220 nm). MS(ES): m/z 429.8 [M+NH₄]⁺.

EXAMPLE 3(3aα,4β,7β,7aα)-2-(3-Chlorophenyl)hexahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(3)

3-Chloroaniline (0.100 g, 0.787 mmol) and3,6-endoxo-3-methylhexahydrophthalic anhydride (0.172 g, 0.945 mmol)were dissolved in AcOH (2.0 mL) and heated at 110° C. for 11 h. Thereaction was then cooled to 25° C., poured into cold saturated aq. K₂CO₃and stirred vigorously for 10 min. The solution was then filtered andrinsed with water. The resulting filtrate was dried in vacuo to give0.118 g (0.404 mmol, 51%) of compound 3 as a white solid. No furtherpurification was needed. HPLC: 99% at 2.510 min (retention time) (YMC S5ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z292.32 [M+H]⁺.

EXAMPLE 4 (3aα,4α,7α,7aα)- and(3aα,4β,7β,7aα)-4-[(Acetyloxy)methyl]-3a,4,7,7a-tetrahydro-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(4i and 4ii, respectively)

2-Acetoxymethylfuran (0.599 mL, 4.78 mmol) and1-[3-(trifluoromethyl)-phenyl]-1H-pyrrole-2,5-dione (0.500 g, 2.39 mmol,prepared as described in Example 1B) were dissolved in methylenechloride (3.0 mL) at 25° C. After 22 h, the volatiles were removed invacuo and the resulting residue was purified by flash chromatography onSiO₂ eluting with 0-15% acetone in methylene chloride to give 0.438 g(1.15 mmol, 48%) of a yellow oil as a 2:1 mixture of compound 4i andcompound 4ii, which was not separated. HPLC: 100% at 3.093 min(retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 398.9 [M+NH₄]⁺.

EXAMPLE 5 (3aα,4α,7α,7aα)- and(3aα,4β,7β,7aα)-4-[(Acetyloxy)methyl]-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(5i and 5ii, respectively)

The 2:1 mixture of compounds 4i and 4ii (0.361 g, 0.948 mmol) wasdissolved in ethyl acetate (25 mL) and Pd/C (10% Pd, 0.2 g) was added.Hydrogen was introduced via a balloon and the reaction was stirred at25° C. for 4 h, followed by filtration through Celite and rinsing withethyl acetate. Concentration in vacuo gave 0.348 g (0.908 mmol, 96%) ofa yellow oil that was determined to be a 2:1 mixture of compound 5i andcompound 5ii (which was not separated). HPLC: 100% at 2.900 min(retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 401.0 [M+NH₄]⁺.

EXAMPLE 6 (3aα,4α,7α,7aα)- and(3aα,4β,7β,7aα)-3a,4,7,7a-Tetrahydro-5-(hydroxymethyl)-2-[3-(trifluoromethyl)phenyl]4,7-epoxy-1H-isoindole-1,3(2H)-dione(6i and 6ii, respectively)

1-[3-(Trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (0.500 g, 2.39 mmol,prepared as described in Example 1B) and 3-furanmethanol (0.412 mL, 4.78mmol) were dissolved in methylene chloride (3.0 mL) and stirred at 25°C. for 20 h. The volatiles were then removed in vacuo and the resultingmaterial purified by flash chromatography on SiO₂ eluting withchloroform/acetone to give 0.379 g (1.12 mmol, 47%) of compound 6i and0.220 g of compound 6ii, both as white solids. Compound 61: HPLC: 100%at 2.197 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 338.0 [M−H]⁻. Compound 6ii: HPLC:100% at 2.477 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4mL/min, monitoring at 220 nm). MS (ES): m/z 338.0 [M−H]⁻.

EXAMPLE 7(3aα,4α,7α,7aα)-3a,4,7,7a-Tetrahydro-5-(hydroxymethyl)-4-methyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(7)

2-Methyl-3-furanmethanol (0.537 g, 4.78 mmol) and1-[3-(trifluoromethyl)-phenyl]-1H-pyrrole-2,5-dione (0.500 g, 2.39 mmol,prepared as described in Example 1B) were dissolved in dichloroethane(2.0 mL) and stirred at 25° C. for 20 h. The reaction was thenconcentrated in vacuo and purified by flash chromatography in SiO₂eluting with ethyl acetate/methylene chloride to give 0.317 g (0.897mmol, 37.5%) of compound 7 as a white solid. No other possible isomerwas isolated after chromatography. HPLC: 100% at 2.197 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 351.9 [M−H]⁻.

EXAMPLE 8(3aα,4β,7β,7aα)-2-[3,5-Bis(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione(8)

3,5-Bis(trifluoromethyl)aniline (0.017 g, 0.075 mmol) was dissolved inacetic acid (0.300 mL) and transferred to a 1.5 mL conical vial with asepta cap. Stock solutions of an additional 95 amines were prepared asdescribed above. To each of the above vials was added 0.40 mL (0.12mmol) of a stock solution ofexo-7-oxabicyclo[2.2.1]heptane-2,-3-dicarboxylic anhydride in aceticacid. The vials were then sealed and heated at 110° C. for 11 h. Uponcooling to 25° C., the caps were removed from the vials and the aceticacid was removed in vacuo. To each vial was added 1 mL of 2:1acetone/methylene chloride and the vials were heated at 40° C. for 1 h.Once all products were in solution, they were transferred via robot tofilter tubes with coarse frits pre-wetted with 0.2 mL of water. Nitrogenwas blown through each tube until the volatile organics were removed.1.5 mL of 10% aq. K₂CO₃ was then added to each tube followed by vigorousshaking at 25° C. for 15 min. The tubes were then drained, resealed and1.0 mL of water was added to each tube followed by shaking. The tubeswere drained again and washed with water a second time. The resultingresidues in each tube were then dried in vacuo for 48 h. After drying,1.0 mL of 20% TFA in methylene chloride was added to each tube and theracks were shaken for 30 min. The tubes were then drained into a 96-wellplate with pre-tared custom micro-tubes present. Each tube was assayedfor product purity (analytical LC) and identity (LC-MS). The tubes werethen concentrated in vacuo and weighed for yields. The tube containingthe reaction of 3,5-bistrifluoromethylaniline andexo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride, yielded 0.022g (0.058 mmol, 77%) of compound 8 as a white solid. HPLC: 94% at 4.03min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 434.2 [M+Na⁺ MeOH]⁺. Of theremaining 95 additional reactions run, a total of 80 final compoundswere obtained in >70% purity and >5 mg yield. Several samples neededfurther purification which was performed by short SiO₂ column elutingwith methylene chloride/acetone. See Table 2 below.

EXAMPLE 9(3aα,4α,7α,7aα)-2-(4-Bromophenyl)octahydro-1,3-dioxo-4,7-etheno-5H-pyrrolo[3,4-c]pyridine-5-carboxylicacid phenyl ester (9)

1-[4-Bromophenyl]-1H-pyrrole-2,5-dione (0.250 g, 0.992 mmol, prepared asdescribed in Example 1B) and 1(2H)-pyridinecarboxylic acid phenylmethylester (0.299 g, 1.49 mmol, synthesized as described in Richard et al. J.Org. Chem. 46, 4836-4842 (1981)) were dissolved in toluene and heated at85° C. for 1 h. Upon cooling to 25° C., the toluene was removed invacuo. The resulting residue was dissolved in a minimum amount ofchloroform and the product was precipitated by addition of hexanes.After 1 h at 25° C., the product was filtered and rinsed with cold 20%hexanes in chloroform giving 0.243 g (0.536 mmol, 54%) of compound 9 asa white solid (single isomer). HPLC: 100% at 3.393 min (retention time)(YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES):m/z 454.98 [M+H]⁺.

EXAMPLE 10(3aα,4α,7α,7aα)-2-(4-Bromophenyl)octahydro-1,3-dioxo-4,7-etheno-5H-Pyrrolo[3,4-c]pyridine-5-carboxylicacid phenylmethyl ester (10)

1-[3-(Trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (3.78 g, 15.7 mmol,prepared as described in Example 1B) and 1(2H)-pyridinecarboxylic acidphenylmethyl ester (4.00 g, 18.8 mmol, synthesized as described inRichard et al. J. Org. Chem. 46, 4836-4842 (1981)) were dissolved intoluene and heated at 80° C. for 3 h. After cooling to 25° C., thetoluene was removed in vacuo and the resulting residue was purified byflash chromatography on SiO₂ eluting with methanol/methylene chloride togive 3.20 g (7.01 mmol, 45%) of compound 10 as a yellow oil. HPLC: 95%at 3.510 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 457.2 [M+H]⁺.

EXAMPLE 11(3aα,4α,7α,7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-Pyrrolo[3,4-c]pyridine-1,3(2H)-dionetrifluoroacetate (11)

Compound 10 (3.20 g, 7.01 mmol) was dissolved in 100 mL of MeOH and 10%Pd/C Degussa catalyst (2.00 g, cat.) was added. Hydrogen was thenintroduced via a balloon. After 1 h, the reaction was filtered throughCelite and rinsed with MeOH. The volatiles were removed in vacuo and theresulting crude material was purified by reverse phase preparative HPLCto yield 2.50 g (5.70 mmol, 81%) of compound 11 as the TFA salt (whitesolid). HPLC: 99% at 1.843 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 325.12 [M+H]⁺.

EXAMPLE 12(3aα,4α,7α,7aα)-5-Acetylhexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione(12)

Compound 11 (0.10 g, 0.23 mmol) was suspended in THF (5.0 mL) and TEA(0.097 mL, 0.46 mmol) was added resulting in a homogeneous solution.Acetyl chloride (0.033 mL, 0.46 mmol) was then added. After 2 h, thereaction was quenched with saturated aqueous NaHCO₃ and extracted withmethylene chloride (3×15 mL). The crude material was purified bypreparative TLC eluting with chloroform/acetone to give 0.067 g (0.18mmol, 79%) of compound 12 as a colorless oil. HPLC: 99% at 2.66 min(retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 367.0 [M+H]⁺.

EXAMPLE 13(3aα,4α,7α,7aα)-5-Benzoylhexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione(13)

Compound 11 (0.10 g, 0.23 mmol) was suspended in THF (5.0 mL) and TEA(0.097 mL, 0.46 mmol) was added resulting in a homogeneous solution.Benzoyl chloride (0.053 mL, 0.46 mmol) was then added. After 2 h, thereaction was quenched with saturated aqueous NaHCO₃ and extracted withmethylene chloride (3×15 mL). The crude material was purified by reversephase preparative HPLC to give 0.020 g (0.047 mmol, 20%) of compound 13as a white foam. HPLC: 99% at 3.183 min (retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 429.1[M+H]⁺.

EXAMPLE 14(3aα,4α,7α,7aα)-Hexahydro-5-methyl-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-pyrrolo[3,4-c]pyridine-1,3(21)-dione(14)

Compound 11 (0.10 g, 0.23 mmol) was suspended in THF (5.0 mL) and TEA(0.097 mL, 0.46 mmol) was added resulting in a homogeneous solution.Dimethyl sulfate (0.043 mL, 0.46 mmol) was added and the reaction wasstirred at 25° C. After 14 h, the reaction was concentrated in vacuo andthe crude material was purified by preparative TLC eluting with 10% MeOHin methylene chloride to give 0.030 g (0.088 mmol, 39%) of compound 14as a white solid. HPLC: 100% at 1.797 min (retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z339.21 [M+H]⁺.

EXAMPLE 15(3aα,4α,7α,7aα)-Hexahydro-5-(Phenylmethyl)-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dionetrifluoroacetate (15)

Compound 11 (0.10 g, 0.23 mmol) was dissolved in DMF (5.0 mL) and K₂CO₃(0.063 g, 0.46 mmol) was added. Benzyl bromide (0.041 mL, 0.35 mmol) wasthen added. The reaction was stirred at 25° C. for 1 h, filtered andconcentrated in vacuo. The crude material was purified by reverse phasepreparative HPLC to give 0.055 g (0.10 mmol, 43%) of compound 15 as awhite solid. HPLC: 100% at 2.31 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 415.36 [M+H]⁺.

EXAMPLE 16(3aα,4α,7α,7aα)-Hexahydro-5-propyl-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dionetrifluoroacetate (16)

Compound 11 (0.10 g, 0.23 mmol) was dissolved in DMF (5.0 mL) and K₂CO₃(0.079 g, 0.57 mmol) was added, followed by 1-bromopropane (0.031 mL,0.34 mmol). The reaction was stirred at 25° C. for 6 h, then filteredand concentrated in vacuo. The crude material was purified by reversephase preparative HPLC to give 0.070 g (0.15 mmol, 63%) of compound 16as a white solid. HPLC: 100% at 1.907 min (retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z340.22 [M+H]⁺.

EXAMPLE 17(3aα,4α,4aβ,5aβ,6α,6aα)-2-[4-Cyano-3-(trifluoromethyl)phenyl]decahydro-1,3-dioxo-4,6-(iminomethano)cycloprop[f]isoindole-7-carboxylicacid phenylmethyl ester (17)

1-Methyl-3-nitro-1-nitrosoguanidine (2.5 g, 17 mmol) was addedportionwise to a solution of 40% KOH/H₂O (15 mL) and Et₂O (25 mL) at 0°C. The ether layer turned yellow once addition was complete. After 30min at 0° C., the ether layer was poured into a solution of(3aα,4α,7α,7aα)-2-[4-cyano-3-(trifluoromethyl)phenyl]-octahydro-1,3-dioxo-4,7-etheno-5H-pyrrolo[3,4-c]pyridine-5-carboxylicacid phenylmethyl ester (0.500 g, 1.09 mmol, prepared as described inExample 10) and Pd(OAc)₂ (0.010 g) in THF (10 mL) at 0° C. The reactionwas then warmed slowly to 25° C., stirred for 24 h and then filteredthrough Celite rinsing with THF. The crude material was then purified byflash chromatography on SiO₂ eluting with MeOH/CH₂Cl₂ to give 0.34 g(0.69 mmol, 63%) of compound 17 as a white solid and a single isomer.HPLC: 100% at 3.61 min (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA,4 mL/min, monitoring at 220 nm). MS (ES): m/z 496.25 [M+H]⁺.

EXAMPLE 18(3aα,4α,4aβ,5aβ,6α,6aα)-4-[Decahydro-1,3-dioxo-4,6-(iminomethano)cycloprop[f]isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(18)

Compound 17 (0.200 g, 0.404 mmol) was dissolved in MeOH (20 mL) and 5%Pd/C (0.200 g) was added. Hydrogen was then introduced via balloon.After 3 h, the reaction was filtered through Celite, rinsed with MeOHand the volatiles were removed in vacuo to yield 0.130 g (0.360 mmol,89%) compound 18 as a white solid. HPLC: 100% at 1.80 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 362.09 [M+H]⁺.

EXAMPLE 19(3aα,4α,4aβ,5aβ,6α,6aα)-4-[Decahydro-7-methyl-1,3-dioxo-4,6-(iminomethano)cycloprop[f]isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(19)

Compound 18 (0.100 g, 0.277 mmol) was dissolved in CH₃CN (2.0 mL). TEA(0.19 mL, 1.4 mmol) and MeI (0.052 mL, 0.83 mmol) were then added andthe reaction was stirred at 25° C. for 14 h. The reaction wasconcentrated under reduced pressure and the crude material was partionedbetween CH₂Cl₂/water and the aqueous layer was extracted with CH₂Cl₂(3×15 mL). The combined organics were dried over anhydrous Na₂SO₄. Thecrude material was purified by flash chromatography eluting with 3%MeOH/CH₂Cl₂ to give 0.030 g (0.080 mmol, 29%) of compound 19 as a lightyellow solid. HPLC: 100% at 1.720 min (retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z376.11 [M+H]⁺.

EXAMPLE 20(3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(20B)

A. (3aα,4β,7β,7aα)-Hexahydro-4,7-epoxyisobenzofuran-1,3-dione (20A)

Freshly distilled dimethyl furan (1.60 mL, 15.3 mmol) was dissolved inCH₂Cl₂ (2.0 mL) and maleic anhydride (1.00 g, 10.2 mmol) was added. Thereaction was stirred at 25° C. for 16 h and was then concentrated invacuo to give a yellow solid. This solid was dissolved in ethyl acetate(30 mL) and 10% Pd/C (0.200 g, cat.) was added. Hydrogen was thenintroduced via a balloon and the reaction stirred for 24 h. The reactionmixture was filtered through Celite rinsing with EtOAc followed byconcentration in vacuo to give 1.69 g (8.61 mmol, 84%) of compound 20Aas a white solid. 2-Dimensional NOE experiments confirmed the structuralassignment to be that of compound 20A.

B.(3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(20B)

A solution of compound 20A (603 mg, 3.21 mmol),5-amino-2-cyanobenzotrifluoride (640 mg, 3.44 mmol) and TsOH (10 mg,cat.) in toluene (5 mL) was heated in a sealed tube for 2 days. Thereaction mixture was cooled to room temperature and then concentratedunder reduced pressure. Purification by flash chromatography on silicagel eluting with 50% EtOAc/hexanes gave 400 mg (1.10 mmol, 34%) ofcompound 20B as a white solid. HPLC: 99% at 3.04 min (retention time)(YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ESI): m/z 382.2 [M+NH₄]⁺.

EXAMPLE 21(3aα,4β,7β,7aα)-N-[4-[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]thio]phenyl]acetamide(21E)

A. 5-Methyl-2-furanethanol (21A)

A solution of n-BuLi (83.0 mL, 133 mmol, 1.6 M in hexanes) was added toa stirred solution of 2-methylfuran (10.0 mL, 111 mmol) in THF (85 mL)at 0° C. under inert atmosphere. The reaction mixture was stirred for 4h at room temperature then cooled to 0° C. Ethylene oxide (8.30 mL, 166mmol) was added dropwise and the reaction mixture was allowed to warm toroom temperature overnight. After quenching with saturated aqueousNH₄Cl, the resulting layers were separated and the aqueous layer wasextracted with Et₂O (2×250 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. Distillation atatmospheric pressure (170-185° C.) gave 10.1 g (80.3 mmol, 72%) ofcompound 21A as a light yellow oil.

B. 2-(2-Bromoethyl)-5-methylfuran (21B)

Ph₃Br₂ (3.68 g, 8.72 mmol) was added to a solution of compound 21A (1.00g, 7.93 mmol) in DMF (8 mL) and the reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was added to H₂O and extractedwith EtOAc (3×). The combined organic layers were washed with H₂O (2×),dried over Na₂SO₄ and concentrated under reduced pressure. Purificationby flash chromatography on silica gel eluting with 10% EtOAc/hexanesgave 0.507 g (2.68 mmol, 34%) of compound 21B.

C. N-[4-[[2-(5-Methyl-2-furanyl)ethyl]thio]phenyl]acetamide (21C)

To a solution of 4-acetamidothiophenol (442 mg, 2.64 mmol) in THF (1 mL)at 0° C. under inert atmosphere was added a solution of n-BuLi (2.00 mL,3.17 mmol, 1.6 M in hexanes) in THF (1 mL). The reaction solution wasstirred at room temperature for 10 min then a solution of compound 21B(500 mg, 2.64 mmol) in THF (3 mL) was added. After the starting materialwas consumed (as determined by TLC), the reaction was quenched with H₂Oand the mixture was extracted with EtOAc (2×), dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with 50% EtOAc/hexanes gave 0.644 g(2.34 mmol, 88%) of compound 21C. MS (ESI): m/z 276.09 [M+H]⁺.

D.(3aα,4β,7β,7aα)-N-[4-[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]-1,2,3,3a,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]thio]phenyl]acetamide(21D)

A solution of compound 21C (195 mg, 0.708 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(377 mg, 1.416 mmol, prepared as described for Example 1B) in CH₂Cl₂(1.5 mL) was stirred at room temperature for two days. The reactionmixture was concentrated under reduced pressure to yield compound 21D asdetermined by NMR analysis. Compound 21D was used directly in the nextstep without purification.

E.(3aα,4β,7β,7aα)-N-[4-[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]-octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]thio]-phenyl]acetamide(21E)

A solution of crude compound 21D (0.708 mmol) and 10% Pd/C (200 mg) inMeOH (20 mL) was stirred under a hydrogen atmosphere overnight.Purification by reverse phase HPLC [34.4 min (retention time) (YMC S5ODS column 20×250 mm, 0-100% aqueous methanol over 30 minutes containing0.1% TFA, 10 mL/min, monitoring at 220 nm)] followed by flashchromatography on silica gel eluting with 1% MeOH/CH₂Cl₂ gave 29 mg(0.053 mmol, 7.5%) of compound 21E as a yellow powder. HPLC: 99% at 3.44min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ESI): m/z 544.01 [M+H]⁺.

EXAMPLE 22(3aα,4β,7β,7aα)-N-[4-[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]sulfinyl]phenyl]acetamide(22)

mCPBA (12 mg, 0.050 mmol) was added portionwise to a solution of crudecompound 21E (65 mg, 0.12 mmol) in CH₂Cl₂ (6 mL) until the startingmaterial was consumed. Purification by reverse phase HPLC [30.5 min(retention time) (YMC S5 ODS column 30×250 mm, 0-100% aqueous methanolover 30 minutes containing 0.1% TFA, 25 mL/min, monitoring at 220 nm)]gave 27.5 mg (0.0491 mmol, 41%) of compound 22 as a tan solid (˜1:1mixture of diastereomers). HPLC: 96% at 2.88 min (retention time) (YMCS5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ESI):m/z 559.97 [M+H]⁺.

EXAMPLE 23(3aα,4β,7β,7aα)-N-[4-[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]sulfonyl]phenyl]acetamide(23)

mCPBA (26 mg, 0.11 mmol) was added to a solution of compound 21E (19 mg,0.035 mmol) in CH₂Cl₂ (6 mL) and the reaction was stirred at rt untilstarting material and the intermediate sulfoxide (compound 22) wereconsumed as was apparent by TLC. Purification by reverse phasepreparative HPLC [53.3 min (retention time) (YMC S5 ODS column 30×250mm, 0-70% aqueous methanol over 45 minutes containing 0.1% TFA, 25mL/min, monitoring at 220 nm)] gave 8.0 mg mg (0.014 mmol, 40%) ofcompound 23 as a white solid. HPLC: 99% at 2.94 min (retention time)(YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ESI): m/z 575.95 [M+H]⁺.

EXAMPLE 24 (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-N-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]benzenesulfonamide(24Ci and 24Cii, respectively)

A. 5-Methyl-2-furanethanol 4-methylbenzenesulfonate (24A)

4-Methylbenzenesulfonyl chloride (907 mg, 4.76 mmol) was added to asolution of compound 21A (500 mg, 3.96 mmol) in 6 mL of dry pyridine.The reaction was stirred at room temperature for 4 h and then quenchedwith ice. The reaction mixture was extracted with CH₂Cl₂ and thecombined organic layers were washed with saturated aqueous sodiumbicarbonate and water, dried and concentrated under reduced pressure togive 900 mg (81%) of compound 24A as a yellow oil.

B. N-[2-(5-Methyl-2-furanyl)ethyl]benzenesulfonamide (24B)

Benzenesulfonamide (157 mg, 1.00 mmol) was added to a 10% aqueoussolution of sodium hydroxide (0.40 mL, 1.0 mmol). A solution of compound24A (280 mg, 1.00 mmol) in acetone (1 mL) was then added. The reactionmixture was heated at 90° C. for 8 h then cooled to room temperature.Ice was added and the mixture was extracted with CH₂Cl₂. The combinedorganic layers were washed with water, dried and concentrated underreduced pressure. Purification by flash chromatography on silica gel,eluting with CH₂Cl₂ gave 60 mg (0.23 mmol, 23%) of compound 24B asyellow oil.

C. (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-N-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]benzenesulfonamide(24Ci and 24Cii, respectively)

4-(2,5-Dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(129 mg, 0.485 mmol, prepared as described in Example 1B) was added to asolution of compound 24B (60 mg, 0.23 mmol) in CH₂Cl₂ (2 mL). Thereaction mixture was stirred at room temperature for 2 days,concentrated under reduced pressure and purified by flash chromatographyon silica gel, eluting with 70% EtOAc/hexanes, to give 20 mg (0.038mmol, 16%) of the unsaturated Diels-Alder product. The unsaturatedproduct (20 mg) was immediately dissolved in ethanol (2 mL) and 10% Pd/C(10 mg, cat.) was added. The solution was stirred at room temperatureovernight under a hydrogen atmosphere. The mixture was filtered and thefiltrate was concentrated under reduced pressure. Purification byreverse phase preparative HPLC gave 7.0 mg (0.013 mmol, 34%) of compound24Ci and 2.0 mg (0.0037 mmol, 10%) of compound 24Cii. Compound 24Ci:HPLC: 96% at 3.17 min (retention time) (YMC ODSA S5 C18 4.6×50 mm,10%-90% aqueous methanol over 4 min gradient with 0.1% TFA, monitoringat 220 nm). MS (ES): m/z: 533.99 [M+H]⁺. Compound 24Cii: HPLC: 99% at38.95 min (retention time) (YMC ODS S5 20×250 mm, 10%-90% aqueousmethanol over 40 min gradient with 0.1% TFA, monitoring at 220 nm). MS(ES): m/z 533.99 [M+H]⁺.

EXAMPLE 25(3aα,4β,7β,7aα)-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(25B)

A. (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-4-[1,3,3a,4,7,7a-Hexahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(25Ai and 25Aii, respectively)

A solution of compound 21A (252 mg, 2.00 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(798 mg, 3.00 mmol) in CH₂Cl₂ (10 mL) was stirred at room temperaturefor 2 days. The reaction mixture was concentrated under reducedpressure. Purification by flash chromatography on silica gel elutingwith 65% EtOAc/hexanes gave 217 mg of pure compound 25Ai, 73 mg of purecompound 25Aii and 310 mg of a mixture of both compound 25Ai and 25Aii.All three fractions were isolated as white solids with a total isolatedyield of 600 mg (1.53 mmol, 76.5%). Compound 25Ai: HPLC: 90% at 2.56 min(retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). Compound 25Aii: HPLC: 90% at 2.56 min (retention time) (YMC S5ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

B.(3aα,4β,7β,7aα)-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(25B)

A solution of compound 25Ai (0.20 g, 0.51 mmol) and 10% Pd/C (43 mg,cat.) in EtOH (12 mL) was stirred under a hydrogen atmosphere at roomtemperature for 2 h. The reaction mixture was filtered through Celiteand concentrated under reduced pressure to give 0.20 g (0.51 mmol, 100%)of compound 25B as a white solid. HPLC: 95% at 2.59 min (retention time)(YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ESI):m/z 394.97 [M+H]⁺.

EXAMPLE 26 (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-N-[4-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-eyoxy-4H-isoindol-4-yl]ethoxy]phenyl]acetamide(26Ci and 26Cii, respectively)

A. 2-[4-[2-(5-Methyl-2-furanyl)ethoxy]phenyl]acetamide (26A)

Triphenylphosphine (681 mg, 2.60 mmol) was added to a solution ofcompound 21A (252 mg, 2.00 mmol) and 4-acetamidophenol (302 mg, 2.00mmol) in CH₂Cl₂ (4 mL). THF (5 mL) was added to make the reactionmixture homogeneous and the mixture was then cooled to 0° C. DEAD (0.41mL, 2.6 mmol) was added dropwise and the reaction mixture was stirred atroom temperature overnight, then concentrated under reduced pressure.Purification by flash chromatography on silica gel eluting with 60%EtOAc/hexanes followed by reverse phase preparative HPLC gave 270 mg(1.04 mmol, 52%) of compound 26A as a light brown solid. MS (ESI): m/z260.09 [M+H]⁺.

B. (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-N-[4-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]-1,2,3,3a,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]phenyl]acetamide(26Bi and 26Bii, respectively)

A solution of compound 26A (40 mg, 0.15 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(88 mg, 0.31 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature for2 days. The reaction mixture was concentrated under reduced pressure.Purification by flash chromatography on silica gel eluting with 75%EtOAc/hexanes gave 55 mg (0.105 mmol, 68%) of a 5:1 mixture of compounds26Bi and 26Bii as a white solid, which was used directly in the nextstep. HPLC: 90% at 3.28 min (retention time) (YMC S5 ODS column 4.6×50mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm).

C. (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-N-[4-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]phenyl]acetamide(26Ci and 26Cii, respectively)

A solution of a mixture of compounds 26Bi and 26Bii (55 mg, 0.105 mmol)and 10% Pd/C (12 mg, cat.) in EtOH (3 mL) was stirred under a hydrogenatmosphere at room temperature overnight. The reaction mixture wasfiltered through Celite and concentrated under reduced pressure to give50 mg of crude product. Purification by flash chromatography on silicagel eluting with 70% EtOAc/hexanes gave 18 mg (0.034 mmol, 32%) ofcompound 26Ci [HPLC: 96% at 3.33 min (retention time) (YMC S5 ODS column4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 528.01[M+H]⁺]; and 2.3 mg (0.0044 mmols, 4%) of an 85:15 mixture of 26Cii and26Ci respectively as determined by ¹H NMR. HPLC: 90% at 3.35 min(retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). MS (ESI): nl/z 528.12 [M+H]⁺.

EXAMPLE 27(3aα,4α,7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(27D)

A. (endo, endo)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid(27A)

Compounds 27A, 27B and 27C were synthesized in accordance with theapproaches described in Sprague et al. J. Med. Chem. 28, 1580-1590(1985). A mixture of furan (100 mL, 1.38 mol) and maleic acid (160 g,1.38 mol) in H₂O (340 mL) was stirred at room temperature for 5 days.The mixture was placed in a separatory funnel and the aqueous layer wasseparated from the layer containing the unreacted furan. The aqueouslayer was treated with charcoal, filtered through Celite and placed inthe refrigerator. The desired product crystallized from solution uponseeding, was filtered, washed with cold water and dried over P₂O₅ togive 70 g (0.38 mol, 28%) of compound 27A as a white solid.

B. (endo, endo)-7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid (27B)

To a solution of compound 27A (69.0 g, 0.375 mol) in EtOH (700 mL) wasadded 10% Pd/C (4.5 g, cat.) and the mixture was shaken under a hydrogenatmosphere at 55 psi until gas uptake ceased. The mixture was filteredthrough Celite and concentrated in vacuo to give 66.0 g (0.355 mol, 95%)of compound 27B as a white solid.

C. (3aα,4α,7α,7aα)-Hexahydro-4,7-epoxyisobenzofuran-1,3-dione (27C)

A solution of compound 27B (66.0 g, 355 mol) in acetyl chloride (300 mL)was refluxed for 1 h. The reaction solution was concentrated in vacuoand the resulting residue was recrystallized from benzene to give 49.2 g(0.292 mol, 82%) of compound 27C as a white solid (>99% endo by H NMR).

D.(3aα,4α,7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(27D)

Compound 27C (45 mg, 0.30 mmol) was combined with 2-aminonaphthalene (47mg, 0.33 mmol) in acetic acid (1 mL) and heated at 115° C. overnight.After the reaction was cooled to rt, a drop of water was added, and theresulting precipitate was filtered. The material was washed withmethanol and dried to provide 65.7 mg (0.224 mmol, 74.7%) of compound27D as a white crystalline solid. HPLC: 99% at 2.68 min (retention time)(YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ESI): m/z 294.0 [M+H]⁺.

EXAMPLE 28(1aα,2β,2aα,5aα,6β,6aα)-Hexahydro-4-(2-naphthalenyl)-2,6-epoxy-3H-oxireno[f]isoindole-3,5(4H)-dione(28B)

A.(1aα,2β,2aα,5aα,6β,6aα)-Tetrahydro-2,6-epoxyoxireno[f]isobenzofuran-3,5(2aH,5aH)-dione(28A)

As described in Yur'ev et al. J. Gen. Chem. U.S.S.R. (Engl. Transl.) 31,772-775 (1961), a solution ofexo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (5.00 g, 30.1mmol), formic acid (10 mL) and hydrogen peroxide (6 mL) was stirred atroom temperature. After 30 min, the reaction was placed in an ice bath(it became exothermic along with gas evolution) and was allowed to warmto room temperature slowly. After stirring overnight, the resultingprecipitate was collected by filtration and washed with glacial aceticacid and dried to yield 3.02 g of a white powder. The crude solid wasboiled in acetyl chloride (100 mL) for 10 hours and the mixture wasconcentrated to ˜20 mL under reduced pressure. The resulting precipitatewas filtered, washed with dioxanes and dried to give 2.37 g (13.0 mmol,43%) of compound 28A as a white powder.

B.(1aα,2β,2aα,5aα,6β,6aα)-Hexahydro-4-(2-naphthalenyl)-2,6-epoxy-3H-oxireno[f]isoindole-3,5(4H)-dione(28B)

Compound 28A (100 mg, 0.520 mmol) was combined with 2-aminonaphthalene(62.1 mg, 0.434 mmol) in acetic acid (2 mL) and heated at 115° C.overnight. After the reaction was allowed to cool to rt, water wasadded, and the resulting precipitate was filtered. The material waswashed sequentially with aqueous K₂CO₃ and water and then dried in avacuum oven to provide 113.7 mg (0.371 mmol, 85.5%) of compound 28B asan off-white crystalline solid. HPLC: 99% at 1.76 min (retention time)(YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ESI): m/z 308.0 [M+H]⁺.

EXAMPLE 29(3aα,4α,7α,7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-3a,4,7,7a-tetrahydro-4,7-dimethyl-4,7-epithio-1H-isoindole-1,3(2H)-dione8-oxide (29)

2,5-Dimethylthiophene (0.048 mL, 0.42 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(0.290 g, 0.625 mmol, prepared as described for Example 1B) weredissolved in CH₂Cl₂ (8.0 mL) and cooled to −20° C. BF₃.Et₂O (0.412 mL,3.36 mmol) was added slowly followed by addition of mCPBA (˜50%, 0.29 g,0.84 mmol). After 2 h at −20° C., the reaction mixture was poured intosaturated aq. NaHCO₃ and extracted with CH₂Cl₂ (3×20 mL) and theorganics dried over anhydrous Na₂SO₄. The crude product was purified byflash chromatography on SiO₂ eluting with 5%-10%-20% EtOAc in CH₂Cl₂ togive 0.119 g (0.265 mmol, 63%) of compound 29 as a white solid. HPLC:91% at 3.303 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ESI): m/z 480.2 [M+H]⁺.

EXAMPLE 30(3aα,4α,7α,7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-3a,4,7,7a-tetrahydro-4,7-epithio-1H-isoindole-1,3(2H)-dione8-oxide (30)

Thiophene (0.375 mL, 4.69 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(0.100 g, 0.313 mmol, prepared as described for Example 1B) weredissolved in CH₂Cl₂ (50 mL), mCPBA (˜50%, 1.62 g, 4.69 mmol) was addedand the resulting mixture was stirred at 25° C. for 3 h.Triphenylphosphine (2.0 g) was then added. After 15 min, the volatileswere removed in vacuo and the resulting residue was dissolved in CH₂Cl₂(200 mL) and washed with saturated aq. NaHCO₃ (3×50 mL) and dried overNa₂SO₄. The crude material was then purified by flash chromatography onSiO₂ eluting with 1%-3%-5% methanol in CH₂Cl₂ to give 0.059 g (0.14mmol, 45%) compound 30 as a white powder. NMR and LC analysis showed asingle diastereomer. HPLC: 100% at 3.437 min (retention time) (YMC S5ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ESI): m/z443.2 [M+H]⁺.

EXAMPLE 31(3aα,4α,7α,7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-imino-1H-isoindole-1,3(2H)-dione(31D)

A. 7-Azabicyclo[2.2.1]hepta-2,5-diene-2,3,7-tricarboxylic acid2,3-dimethyl 7-(1,1-dimethylethyl) ester (31A)

Freshly distilled acetylenedicarboxylic acid dimethyl ester (6.7 mL, 54mmol) and N-(tert-butyloxycarbonyl)-1H-pyrrole (9.0 mL, 54 mmol) werecombined and heated at 120° C. for 3 h. Purification by flashchromatography on SiO₂ eluting with EtOAc/CH₂Cl₂ gave 8.3 g (27 mmol,50%) of compound 31A as a yellow solid.

B. (exo,endo)-7-Azabicyclo[2.2.1]hept-2,5-diene-2,3,7-tricarboxylic acid7-(1,1-dimethylethyl) ester (31B)

Compound 31A (1.0 g, 3.5 mmol) was dissolved in MeOH (2.0 mL) and aq.KOH (1 g in 5 mL H₂O) was added. The reaction was heated at 50° C. for 1h. The reaction was then cooled to 25° C. and 10% Pd/C (0.5 g, cat.) wasadded and the mixture was placed in a Parr apparatus for 14 h at 25° C.The reaction was then filtered through Celite rinsing with water. Theaqueous solution was acidified to pH 2 by addition of 1 N HCl and thenextracted with EtOAc (2×100 mL). Concentration of the organics gave thecompound 31B as a pale yellow solid.

C.(3aα,4α,7α,7aα)-Hexahydro-1,3-dioxo-4,7-iminoisobenzofuran-8-carboxylicacid 1,1-dimethylethyl ester (31C)

Crude compound, 31B, was heated to 120° C. in vacuo in a sublimationchamber, resulting in sublimation of 0.051 g (0.19 mmol, 5.4%) ofcompound 31C as a white solid, which was collected directly and used inthe next step without further purification.

D.(3aα,4α,7α,7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-imino-1H-isoindole-1,3(2H)-dione(31D)

Compound 31C (0.050 g, 0.19 mmol) and the1-amino-3-(trifluoromethyl)benzene (0.030 g, 0.19 mmol) were dissolvedin AcOH (2.5 mL) and heated at 115° C. for 4.5 h. The reaction wasquenched by addition of saturated aqueous NaHCO₃ and the mixture wasextracted with methylene chloride (3×15 mL). The crude material waspurified by reverse phase preparative HPLC to give 0.030 g (0.097 mmol,51%) of compound 31D as a white solid. HPLC: 99% at 2.33 min (retentiontime) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ESI): m/z 311.15 [M+H]⁺.

EXAMPLE 32 (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-3a,4,7,7a-Tetrahydro-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(32i and 32ii, respectively)

Freshly distilled 2,5-dimethylfuran (0.32 mL, 2.6 mmol) was dissolved inCH₂Cl₂ (2.0 mL) and 1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione(0.5 g, 2.5 mmol, prepared as described in Example 1B) was added. Thereaction was stirred at 25° C. for 16 h and was then concentrated underreduced pressure. Purification by flash chromatography on silica geleluting with 0.5% MeOH/CH₂Cl₂ gave 250 mg (0.741 mmol, 30%) of compound32i, and 50 mg (0.15 mmol, 6%) of compound 32ii as white solids.Compound 32i: HPLC: 98% at 3.080 min (retention time) (YMC S5 ODS column4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 338.30,[M+H]⁺. Compound 32ii: HPLC: 92% at 3.047 min (retention time) (YMC S5ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ES): m/z:338.15 [M+H]⁺.

EXAMPLE 33(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(33)

Compound 32i (0.080 g, 0.24 mmol) was dissolved in EtOAc (2 mL) and EtOH(1 mL) and 10% Pd/C (0.050 g, cat.) was added. Hydrogen was thenintroduced by a balloon and the reaction was stirred for 24 h. Themixture was filtered through Celite, rinsed with EtOAc and concentratedin vacuo to give 0.075 g (0.22 mmol, 93%) of compound 33 as a whitesolid. No further purification was needed. HPLC: 90% at 3.233 min(retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). MS (ES): m/z 340.40 [M+H]⁺.

EXAMPLE 34(3aα,4β,7β,7aα)-Tetrahydro-5-methyl-2-(4-nitro-1-naphthalenyl)-4,7-etheno-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-trione(34B)

A.4,5,7,7a-Tetrahydro-5-methyl-4,7-ethenofuro[3,4-c]pyridine-1,3,6(3aH)-trione(34A)

Compound 34A was synthesized by a modification of the methods describedby Tomisawa et al. Heterocycles 6, 1765-1766 (1977) & Tetrahedron Lett.29, 2465-2468 (1969). Maleic anhydride (2.00 g, 20.4 mmol) and1-methyl-2-pyridone (2.22 g, 20.4 mmol) were suspended in 30 mL ofanhydrous toluene. The reaction vessel was fitted with a Dean Stark trapand refluxed for 48 hours. The dark colored solution was allowed to coolto rt and then the volatiles were removed in vacuo. The resulting brownpaste (4 g) was dissolved in 10 mL of boiling toluene and the hotsolution was filtered under a nitrogen flow to remove particulates. Onstanding at 25° C. the desired product precipitated from solution. Thesolid was isolated by filtration and washed with cold toluene to give1.0 g (4.8 mmol, 24%) of compound 34A, which was used without furtherpurification.

B.(3aα,4α,7α,7aα)-Tetrahydro-5-methyl-2-(4-nitro-1-naphthalenyl)-4,7-etheno-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-trione(34B)

1-Amino-4-nitronaphthalene (0.094 g, 0.50 mmol) and compound 34A (0.130g, 0.627 mmol) were dissolved in AcOH (2.0 mL) and heated at 110° C. for11 h. The reaction was then cooled to 25° C. and poured into coldsaturated aqueous K₂CO₃ and stirred vigorously for 10 min. The solutionwas filtered and rinsed with water. The resulting filtrate wasconcentrated in vacuo and purified by flash chromatography on silica geleluting with 4:6 EtOAc/hexanes to give 0.172 g (0.456 mmol, 91%) ofcompound 34B as a white solid. HPLC: 92% at 2.472 min (retention time)(YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES):m/z 378.29 [M+H]⁺.

EXAMPLE 35(3aα,4β,7β,7aα)-4-[4-[2-(4-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(35)

DEAD (0.060 mL, 0.38 mmol) was added to a solution of triphenylphosphine(100 mg, 0.380 mmol) in THF (1.3 mL) at room temperature under an inertatmosphere. After stirring for 10 min, 4-fluorophenol (43 mg, 0.380mmol) was added in one portion. The reaction mixture was stirred for 5min, compound 25B (100 mg, 0.254 mmol) was added and stirring wascontinued for 3.5 h. Purification by flash chromatography on silica geleluting with 50% EtOAc/hexanes followed by reverse phase preparativeHPLC [11.93 min (retention time) (YMC S5 ODS column 20×100 mm, 0-100%aqueous methanol over 10 minutes containing 0.1% TFA, 20 mL/min,monitoring at 220 nm)] gave 72 mg (58%) of compound 35 as a solid. HPLC:99% at 3.74 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ESI): m/z 487.1 [M−H]⁻.

EXAMPLE 36(3aα,4β,7β,7aα)-4-[4-(2-Bromoethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(36)

A solution of 25B (495 mg, 1.26 mmol) and pyridine (100 μL, 1.26 mmol)in CH₂Cl₂ (2 mL) was added to a solution of Ph₃PBr₂ (636 mg, 1.51 mmol)in CH₂Cl₂ (2 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 3 hr, then the solvent was removed under reducedpressure. The resulting residue was washed 2× with 10 mL portions ofEtOAc-hexane (6:4) and the combined washings were purified by flashchromatography on silica gel eluting with 60% EtOAc/hexane to give 390mg (0.853 mmol, 67.7%) of compound 36 as a white solid. HPLC: 99% at3.51 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ESI): m/z 456.7 [M−H]⁻.

EXAMPLE 37(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(3-methyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(37)

A combination of 4-nitro-3-methylaniline (0.050 g, 0.33 mmol), compound20A (0.083 g, 0.43 mmol), TEA (0.2 mL), MgSO₄ (0.075 g) and toluene (0.8mL) were combined in a sealed tube and the mixture was heated at 120° C.for 14 h. After cooling to 25° C., the reaction was filtered, rinsedwith CH₂Cl₂ and concentrated under reduced pressure. The crude productwas purified by preparative TLC on SiO₂ eluting with CH₂Cl₂ to give0.075 g (0.23 mmol, 69%) of compound 37 as a pale yellow solid. HPLC:100% at 2.733 min (retention time) (YMC S5 ODS column, 4.6×50 mm; 10-90%MeOH/H₂O gradient,+0.1% TFA; 4 mL/min, 220 nm detection). MS (ES): m/z348.2 [M+NH₄]⁺.

EXAMPLES 38 TO 121

Additional compounds of the present invention were prepared byprocedures analogous to those described above. The compounds of Examples38 to 121 have the following structure (L is a bond):

where G, the compound name, retention time, molecular mass, and theprocedure employed, are set forth in Table 2. The chromatographytechniques used to determine the compound retention times of Table 2 areas follows: LCMS=YMC S5 ODS column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.10% TFA; 4 mL/min, monitoring at220 nm. The molecular mass of the compounds listed in Table 2, whereprovided, were determined by MS (ES) by the formula m/z.

TABLE 2 Ex. Compound Retention Time Pro. No. G Name (Min.)/MolecularMass of Ex. 38

(3aα,4β,7β,7aα)-2-(2-Fluorenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.72LCMS/332.20[M + H]⁺ 8 39

(3aα,4β,7β,7aα)-2-[3-Chloro-4-(4-morpholinyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.20LCMS/363.20[M + H]⁺ 8 40

(3aα,4β,7β,7aα)-2-(2,3-Dihydro-1H-inden-5-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.26LCMS/284.22[M + H]⁺ 8 41

(3aα,4β,7β,7aα)-2-(4-Bromo-1-naphthalenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.73LCMS/404.11[M + CH₃OH + H]⁺ 8 42

(3aα,4β,7β,7aα)-2-(4-Chloro-1-naphthalenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.63LCMS/328.14[M + H]⁺ 8 43

(3aα,4β,7β,7aα)-2-(5-Amino-1-naphthalenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione1.64LCMS/ 8 44

(3aα,4β,7β,7aα)-Hexahydro-2-(7-hydroxy-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.54LCMS/308.23[M − H]⁻ 8 45

(3aα,4β,7β,7aα)-Hexahydro-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.117LCMS/404.11[M + CH₃OH + H]⁺ 8 46

(3aα,4β,7β,7aα)-Hexahydro-2-(1H-indol-5-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.39LCMS/283.23[M + H]⁺ 8 47

(3aα,4β,7β,7aα)-Hexahydro-2-(1H-indazol-6-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.35LCMS/282.23[M − H]⁻ 8 48

(3aα,4β,7β,7aα)-2-(1,3-Benzodioxol-5-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.47LCMS/288.20[M + H]⁺ 8 49

(3aα,4β,7β,7aα)-2-[4-Amino-3-(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.71LCMS/327.20[M + H]⁺ 8 50

(3aα,4β,7β,7aα)-2-(3-Chloro-4-iodophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.70LCMS/435.2[M + CH₃OH]⁺ 8 51

(3aα,4β,7β,7aα)-Hexahydro-2-(8-quinolinyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.28LCMS/295.22[M + H]⁺ 8 52

(3aα,4β,7β,7aα)-2-(2,3-Dihydro-1,4-benzodioxin-6-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.55LCMS/302.23[M + H]⁺ 8 53

(3aα,4β,7β,7aα)-Hexahydro-2-[2-oxo-4-(trifluoromethyl)-2H-1-benzopyran-7-yl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.38LCMS/412.17[M + CH₃OH + H]⁺ 8 54

(3aα,4β,7β,7aα)-Hexahydro-2-(4-methyl-2-oxo-2H-1-benzopyran-7-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.74LCMS/326.20[M + H]⁺ 8 55

(3aα,4β,7β,7aα)-2-(2,5-Dimethoxy-4-nitrophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.70LCMS/349.23[M + H]⁺ 8 56

(3aα,4β,7β,7aα)-2,3,5,6-Tetrafluoro-4-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile2.97LCMS 8 57

(3aα,4β,7β,7aα)-Hexahydro-2-(2,4,5-trifluorophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.90LCMS 8 58

(3aα,4β,7β,7aα)-Hexahydro-2-(2,4,5-trichlorophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.64LCMS/346.39[M]⁺ 8 59

(3aα,4β,7β,7aα)-2-(2-Amino-4,5-dichlorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.23LCMS 8 60

(3aα,4β,7β,7aα)-2-(3,4-Difluorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.91LCMS/280.23[M + H]⁺ 8 61

(3aα,4β,7β,7aα)-1-Acetyl-2,3-dihydro-6-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-1H-indole2.43LCMS/359.26[M + CH₃OH + H]⁺ 8 62

(3aα,4β,7β7aα)-2-(3-Chloro-4-fluorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.21LCMS/328.14[M + CH₃OH + H]⁺ 8 63

(3aα,4β,7β,7aα)-2-(3,4-Dichlorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.54LCMS/311.79[M − H]⁻ 8 64

(3aα,4β,7β,7aα)-Hexahydro-2-(3,4,5-trichlorophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione4.05LCMS/378.10[M + CH₃OH + H]⁺ 8 65

(3aα,4β,7β,7aα)-2-(3-Chloro-4-methoxyphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.99LCMS/308.11[M + H]⁺ 8 66

(3aα,4β,7β,7aα)-2-(3-Chloro-4-methylphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.39LCMS/292.20[M + H]⁺ 8 67

(3aα,4β,7β,7aα)-Hexahydro-2-(2-methyl-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.28LCMS/308.23[M + H]⁺ 8 68

(3aα,4β,7β,7aα)-2-(4-Chloro-3-methylphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.40LCMS/292.20[M + H]⁺ 8 69

(3aα,4β,7β,7aα)-2-(3,4-Dimethylphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.11LCMS/272.23[M + H]⁺ 8 70

(3aα,4β,7β,7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.76LCMS/421.98[M + CH₃OH + H]⁺ 8 71

(3aα,4β,7β,7aα)-2-(4-Bromo-3-methylphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.50LCMS/336.05[M + H]⁺ 8 72

(3aα,4β,7β,7aα)-2-(4-Fluoro-3-nitrophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.80LCMS/305.25[M − H]⁻ 8 73

(3aα,4β,7β,7aα)-2-[4-Fluoro-3-(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.45LCMS/362.26[M + CH₃OH + H]⁺ 8 74

(3aα,4β,7β,7aα)-2-(4-Chloro-3-nitrophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.19LCMS/322.86[M]⁺ 8 75

(3aα,4β,7β,7aα)-2-[4-Chloro-3-(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.68LCMS/345.83[M]⁺ 8 76

(3aα,4β,7β,7aα)-2-(4-Chloro-2-methoxy-5-methylphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.31LCMS/322.20[M + H]⁺ 8 77

(3aα,4β,7β,7aα)-2-(4-Amino-3-nitrophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.34LCMS/302.27[M − H]⁻ 8 78

(3aα,4β,7β,7aα)-Hexahydro-2-(4-methyl-3-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.02LCMS/335.20[M + CH₃OH + H]⁺ 8 79

(3aα,4β,7β,7aα)-2-(3,4-Dimethoxyphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.35LCMS/304.25[M + H]⁺ 8 80

(3aα,4β,7β,7aα)-Hexahydro-2-(3-hydroxy-4-methoxyphenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione0.98LCMS/321.19[M + CH₃OH]⁺ 8 81

(3aα,4β,7β,7aα)-Hexahydro-2-(4-methyl-5-nitro-2-pyridinyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione0.54LCMS/304.20[M + H]⁺ 8 82

(3aα,4β,7β,7aα)-2-Chloro-4-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-α-phenylbenzeneacetonitrile3.67LCMS/423.8[M + CH₃OH]⁺ 8 83

(3aα,4β,7β,7aα)-Hexahydro-2-(2-methoxy-3-dibenzofuranyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.66LCMS/364.25[M + H]⁺ 8 84

(3aα,4β,7β,7aα)-Hexahydro-2-(2,3,4-trifluorophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.06LCMS/298.14[M + H]⁺ 8 85

(3aα,4β,7β,7aα)-2-(2,3-Dihydro-2-methyl-1,3-dioxo-1H-isoindol-5-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.70LCMS/359.22[M + CH₃OH + H]⁺ 8 86

(3a,4β,7β,7aα)-2-(4-Bromo-2,3,5,6-tetrafluorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.72LCMS/426.07[M + CH₃OH + H]⁺ 8 87

(3aα,4β,7β,7aα)-Hexahydro-2-(2-hydroxy-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.52LCMS/308.26[M − H]⁻ 8 88

(3aα,4β,7β,7aα)-2-[2,5-Dichloro-4-(1H-pyrrol-1-yl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.70LCMS/376.64[M − H]⁻ 8 89

(3aα,4β,7β,7aα)-Hexahydro-2-[4-(methoxymethyl)-2-oxo-2H-1-benzopyran-7-yl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.79LCMS/356.26[M + H]⁺ 8 90

(3aα,4β,7β,7aα)-2-(6-Benzothiazolyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.46LCMS/301.19[M + H]⁺ 8 91

(3aα,4β,7β,7aα)-2-Methoxy-4-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzoicacid methylester 2.75LCMS/332.25[M + H]⁺ 8 92

(3aα,4β,7β,7aα)-2-Methyl-5-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile2.80LCMS/315.26[M + CH₃OH + H]⁺ 8 93

(3aα,4β,7β,7aα)-Hexahydro-2-(2-oxo-2H-1-benzopyran-6-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.45LCMS/312.20[M + H]⁺ 8 94

(3aα,4β,7β,7aα)-Hexahydro-2-(2,3,5,6-tetramethyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.59LCMS/377.25[M + CH₃OH + H]⁺ 8 95

(3aα,4β,7β,7aα)-Hexahydro-2-(2,4,5-trimethylphenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.33LCMS/286.30[M + H]⁺ 8 96

(3aα,4β,7β,7aα)-2-(4-Fluoro-3-methylphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.00LCMS/276.23[M + H]⁺ 8 97

(3aα,4β,7β,7aα)-Hexahydro-2-(3-methoxy-4-methylphenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.05LCMS/288.23[M + H]⁺ 8 98

(3aα,4β,7β,7aα)-N-Ethyl-2-methyl-5-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-N-phenylbenzenesulfonamide3.56LCMS/441.26[M + H]⁺ 8 99

(3aα,4β,7β,7aα)-2,6-Dibromo-4-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzenesulfonamide2.25LCMS 8 100

(3aα,4β,7β,7aα)-2,4-Dimethyl-6-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-pyridinecarbonitrile2.75LCMS/298.23[M + H]⁺ 8 101

(3aα,4β,7β,7aα)-2-(2,3-Dimethyl-1H-indol-5-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.00LCMS/311.26[M + H]⁺ 8 102

(3aα,4β,7β,7aα)-2-(3-Dibenzofuranyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.72LCMS/366.23[M + CH₃OH + H]⁺ 8 103

(3aα,4β,7β,7aα)-Hexahydro-2-(2′-hydroxy[1,1′:3′,1″-terphenyl]-5′-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.70LCMS/412.23[M + H]⁺ 8 104

(3aα,4β,7β,7aα)-Hexahydro-2-(5,6,7,8-tetrahydro-3-hydroxy-2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.24LCMS/312.32[M + H]⁺ 8 105

(3aα,4β,7β,7aα)-2-(2,3-Dihydro-1H-indol-6-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.42LCMS/285.29[M + H]⁺ 8 106

(3aα,4β,7β,7aα)-2-(1,3-Dihydro-2,2-dioxidobenzo[c]thiophen-5-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione1.99LCMS/366.26[M + CH₃OH + H]⁺ 8 107

(3aα,4β,7β,7aα)-Hexahydro-2-(2-hydroxy-4,5-dimethylphenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.78LCMS/286.32[M − H]⁻ 8 108

(3aα,4β,7β,7aα)-2-(2,3-Dihydro-2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.82LCMS/406.19[M + CH₃OH + H]⁺ 8 109

(3aα,4β,7β,7aα)-Hexahydro-2-(1H-indazol-5-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.13LCMS/284.23[M + H]⁺ 8 110

(3aα,4β,7β,7aα)-2-(4-Amino-2,3,5,6-tetrafluorophenyl)-hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.60LCMS/363.22[M + CH₃OH + H]⁺ 8 111

(3aα,4β,7β,7aα)-2-(4-Bromo-3-chlorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.64LCMS/389.64[M + CH₃OH + H]⁺ 8 112

(3aα,4β,7β,7aα)-Hexahydro-2-(5-hydroxy-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.48LCMS/308.27[M − H]⁻ 8 113

(3aα,4β,7β,7aα)-4-(Octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile3.28LCMS/337.16[M + H]⁺ 8 114

(3aα,4β,7β,7aα)-2-(4-Morpholinyl)-5-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzoicacid methylester 2.72LCMS/387.17[M + H]⁺ 8 115

(3aα,4β,7β,7aα)-2-Fluoro-5-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile2.69LCMS/319.26[M + CH₃OH + H]⁺ 8 116

(3aα,4β,7β,7aα)-2-(4-Bromophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione5.80LCMS/393.0[M + H]⁺ 8 117

(3aα,4β,7β,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione6.92LCMS/333.7[M + H]⁺ 8 118

(3aα,4β,7β,7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.27LCMS/312.2[M + H]⁺ 8 119

(3aα,4β,7β,7aα)-Hexahydro-2-(4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.88LCMS/343.2[M + H]⁺ 8 120

(3aα,4β,7β,7aα)-2-(9-Ethyl-9H-carbazol-3-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.73LCMS/360.1[M + H]⁺ 8 121

(3aα,4β,7β,7aα)-2-[1,2-Dihydro-8-methyl-2-oxo-4-(trifluoromethyl)-7-quinolinyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.11LCMS/393.0[M + H]⁺ 8

EXAMPLES 122 TO 164

Further compounds of the present invention were prepared by proceduresanalogous to those described above. Table 3 provides the compound nameand structure, retention time, as well as the Example number of theprocedure on which the preparation of Table 3 was based, for thecompounds of Examples 122 to 164. The chromatography techniques used todetermine the compound retention times of Table 3 are as follows:

LCMS=YMC S5 ODS column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.

LC=YMC S5 ODS column 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm

TABLE 3 Compound Compound Retention Time Ex. No. Structure NameMin./Molecular Mass Pro. of Ex. 122

(3aα,4α,7α,7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.66LCMS 27 123

(3aα,4α,7α,7aα)-Hexahydro-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.76LCMS 27 124

(3aα,4β,7β,7aα)-2-(4-Bromo-3-methylphenyl)-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione6.36LCMS 8 125

(3aα,4β,7β,7aα)-2-(4-Bromophenyl)-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione5.72LCMS 8 126

(3aα,4β,7β,7aα)-3a,4,7,7a-Tetrahydro-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione5.92LCMS 8 127

(3aα,4β,7β,7aα)-2-(9-Ethyl-9H-carbazol-3-yl)-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.73LCMS 8 128

(3aα,4β,7β,7aα)-2-[4-Fluoro-3-(trifluoromethyl)phenyl]-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.40LCMS 8 129

(3aα,4β,7β,7aα)-2-[1,2-Dihydro-8-methyl-2-oxo-4-(trifluoromethyl)-7-quinolinyl]-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.14LCMS 8 130

(3aα,4α,7α,7aα)-4-[(Acetyloxy)methyl]-2-(4-bromo-3-methylphenyl)-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.95LC 4 131

(3aα,4β,7β,7aα)-4-[(Acetyloxy)methyl]-2-(4-bromo-3-methylphenyl)-3a,47,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.97LCMS 5 132

(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.08LC 20 133

(3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-1-naphthalenecarbonitrile3.00LC 20 134

(3aα,4β,7β,7aα)-(Benzo[b]thiophen-3-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.61LC 20 135

(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.21LC 20 136

(3aα,4β,7β,7aα)-4-(1,3,3a,4,7,7a-Hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-1-naphthalenecarbonitrile2.94LC 32 137

(3aα,4α,7α,7aα)-Hexahydro-4-methyl-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.88LC 3 138

(3aα,4β,7β,7aα)-2-(4-Bromo-3-methylphenyl)hexahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.11LC 3 139

(3aα,4β,7β,7aα)-Hexahydro-4-methyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.90LC 3 140

(3aα,4β,7β,7aα)-2-(3,5-Dichlorophenyl)hexahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.31LC 3 141

(3aα,4β,7β,7aα)-2-(3-Chloro-4-fluorophenyl)-hexahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.72LC 3 142

(3aα,4β,7β,7aα)-2-Methoxy-4-(octahydro-1,3-dioxo-4-methyl-4,7-epoxy-2H-isoindol-2-yl)-1-naphthalenecarbonitrile2.72LC 3 143

(3aα,4β,7β,7aα)-Hexahydro-4-methyl-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.10LC 3 144

(3aα,4β,7β,7aα)-Hexahydro-2-[4-(1H-imidazol-1-yl)phenyl]-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione1.16LC 3 145

(3aα,4β,7β,7aα)-2-[3-Chloro-4-(2-thiazolyl)phenyl]hexahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.81LC 3 146

(3aα,4α,7α,7aα)-2-(3,5-Dichlorophenyl)hexahydro-4,7-imino-1H-isoindole-1,3(2H)-dione2.72LC 31 147

(3aα,4α,7α,7aα)-2-(4-Bromo-1-naphthalenyl)hexahydro-4,7-imino-1H-isoindole-1,3(2H)-dione2.95LC 31 148

(3aα,4α,7α,7aα)-2-(4-Bromo-3-methylphenyl)hexahydro-4,7-imino-1H-isoindole-1,3(2H)-dione2.65LC 31 149

(3aα,4α,7α,7aα)-Hexahydro-2-(4-nitro-1-naphthalenyl)-4,7-imino-1H-isoindole-1,3(2H)-dione2.49LC 31 150

(3aα,4α,7α,7aα)-8-Acetyl-2-(3,5-dichlorophenyl)hexahydro-4,7-imino-1H-isoindole-1,3(2H)-dione3.53LC 31, 12 151

(3aα,4α,7α,7aα)-Octahydro-1,3-dioxo-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-5H-pyrrolo[3,4-c]pyridine-5-carboxylicacidphenyl ester  3.397LC 9 152

(3aα,4α,7α,7aα)-4-(Octahydro-1,3-dioxo-4,7-ethano-2H-pyrrolo[3,4-naphthalenecarbonitrile1.74LC 11 153

(3aα,4α,7α,7aα)-4-(Octahydro-5-methyl-1,3-dioxo-4,7-ethano-2H-pyrrolo[3,4-c]pyridin-2-yl)-1-naphthalenecarbonitrile1.71LC 14 154

(3aα,4α,7α,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-1,3-dioxo-4,7-etheno-5H-pyrrolo[3,4-c]pyridine-5-carboxylicacid phenylmethylester 3.40LC 10 155

(3aα,4α,7α,7aα)-4-(Octahydro-1,3-dioxo-4,7-ethano-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-(trifluoromethyl)benzonitrile1.74LC 11 156

(3aα,4α,7α,7aα)-4-(Octahydro-5-methyl-1,3-dioxo-4,7-ethano-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-(trifluoromethyl)benzonitrile1.65LC 14 157

(3aα,4α,7α,7aα)-2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-1,3-dioxo-4,7-etheno-5H-pyrrolo[3,4-c]pyridine-5-carboxylicacid phenylmethylester 3.53LC 10 158

(3aα,4α,7α,7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]tetrahydro-5-methyl-4,7-etheno-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-trione2.95LCMS 34 159

(3aα,4α,7α,7aα)-Tetrahydro-5-methyl-2-[3-(trifluoromethyl)phenyl]-4,7-etheno-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-trione2.53LCMS 34 160

(3aα,4α,7α,7aα)-Tetrahydro-5-methyl-2-(2-naphthalenyl)-4,7-etheno-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-trione2.58LCMS 34 161

(1aα,2β,2aα,5aα,6β,6aα)-Hexahydro-4-[3-(trifluoromethyl)phenyl]-2,6-epoxy-3H-oxireno[f]iso-indole-3,5(4H)-dione1.80LCMS 28 162

(1aα,2β,2aα,5aα,6β,6aα)-4-(3,5-Dichlorophenyl)-hexahydro-2,6-epoxy-3H-oxireno[f]isoindole-3,5(4H)-dione1.45LCMS 28 163

(1aα,2β,2aα,5aα,6β,6aα)-Hexahydro-4-(4-nitro-1-naphthalenyl)-2,6-epoxy-3H-oxireno[f]isoindole-3,5(4H)-dione1.52LCMS 28 164

(1aα,2β,2aα,5aα,6β,6aα)-4-(3,4-Dichlorophenyl)-hexahydro-2,6-epoxy-3H-oxireno[f]isoindole-3,5(4H)-dione3.21LCMS 28

EXAMPLES 165 TO 203

Additional compounds of the present invention were prepared and aredescribed further below in Table 4. Table 4 sets forth the compound nameand structure, as well as the Example number of the procedure on whichthe preparation of Table 4 was based, for the compounds of Examples 165to 203.

TABLE 4 Ex. Compound Compound Pro. No. Structure Name of Ex. 165

2-[4-(4-Bromo-phenoxy)phenyl]-3a,4,7,7a-tetrahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 166

3a,4,7,7a-Tetrahydro-2-(2-methoxyphenyl)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 167

[(1,2,3,3a,7,7a-Hexahydro-2-phenyl-4,7-epoxy-4H-isoindol-4-yl)methyl]carbamicacid(3,5-dimethoxyphenyl)methyl ester 21-26 168

2-(2,4-Dimethylphenyl)-3a,4,7,7a-tetrahydro-4-(hydroxymethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26 169

2-(1,3-Benzodioxol-5-yl)-3a,4,7,7a-tetrahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 170

4-[Bis(acetyloxy)methyl]-2-(3-bromophenyl)-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26 171

N-[[1,2,3,3a,7,7a-Hexahydro-2-(2,4,6-trimethylphenyl)-4,7-epoxy-4H-isoindol-4-yl]methyl]-2,2-dimethylpropanamide21-26 172

3a,4,7,7a-Tetrahydro-4-(hydroxymethyl)-2-[2-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26 173

3a,4,7,7a-Tetrahydro-4-(hydroxymethyl)-2-(1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26 174

2-Chloro-5-(1,3,3a,4,7,7a-hexahydro-4,7-dimethyl-4,7-epoxy-2H-isoindol-2-yl)benzoicacid methylester 32 175

4-[Bis(acetyloxy)methyl]-2-(4-bromo-2-nitrophenyl)-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26 176

3a,4,7,7a-Tetrahydro-4-methyl-2-(4-methyl-3-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 177

2-[2-Chloro-5-(trifluoromethyl)phenyl]-3a,4,7,7a-tetrahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 178

2-[4-Chloro-3-(trifluoromethyl)phenyl]-3a,4,7,7a-tetrahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 179

2-(1,3,3a,4,7,7a-Hexahydro-4-methyl-4,7-epoxy-2H-isoindol-2-yl)benzonitrile32 180

2-(4-Fluorophenyl)-3a,4,7,7a-tetrahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 181

2,2,2-Trifluoro-N-[(1,2,3,3a,7,7a-hexahydro-2-phenyl-4,7-epoxy-4H-isoindol-4-yl)methyl]acetamide21-26 182

3a,4,7,7a-Tetrahydro-4,7-dimethyl-2-(4-methyl-3-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 183

2-Chloro-5-[1,3,3a,4,7,7a-hexahydro-4-(hydroxymethyl)-4,7-epoxy-2H-isoindol-2-yl]benzoicacid 21-26 184

3a,4,7,7a-Tetrahydro-4,7-dimethyl-2-(4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 185

3a,4,7,7a-Tetrahydro-2-(2-mercaptophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 186

3a,4,7,7a-Tetrahydro-2-[2-[(phenylmethyl)thio]phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione32 187

[[2-(4-Chlorophenyl)-1,2,3,3a,7,7a-hexahydro-4,7-epoxy-4H-isoindol-4-yl]methyl]carbamicacid2-methylpropylester 21-26 188

4-(1,1-Dimethylethyl)-N-[[1,2,3,3a,7,7a-hexahydro-2-(4-methylphenyl)-4,7-epoxy-4H-isoindol-4-yl]methyl]benzamide21-26 189

2,4-Dichloro-N-[[1,2,3,3a,7,7a-hexahydro-2-(4-nitrophenyl)-4,7-epoxy-4H-isoindol-4-yl]methyl]benzamide21-26 190

N-[[2-(4-Chlorophenyl)-1,2,3,3a,7,7a-hexahydro-4,7-epoxy-4H-isoindol-4-yl]methyl]-2,4,6-trimethylbenzenesulfonamide21-26 191

N-[[1,2,3,3a,7,7a-Hexahydro-2-(4-nitrophenyl)-4,7-epoxy-4H-isoindol-4-yl]methyl]-2,2-dimethylpropanamide21-26 192

N-[(1,2,3,3a,7,7a-Hexahydro-2-phenyl-4,7-epoxy-4H-isoindol-4-yl)methyl]-2-phenoxyacetamide21-26 193

[(1,2,3,3a7,7a-Hexahydro-2-phenyl-4,7-epoxy-4H-isoindol-4-yl)methyl]carbamicacid1,1-dimethylethylester 21-26 194

2-(2,4-Dichlorophenoxy)-N-[[1,2,3,3a,7,7a-hexahydro-2-(4-nitrophenyl)-4,7-epoxy-4H-isoindol-4-yl]methyl]acetamide21-26 195

N-[[1,2,3,3a,7,7a-Hexahydro-2-(4-methylphenyl)-4,7-epoxy-4H-isoindol-4-yl]methyl]-3,5-dimethoxybenzamide21-26 196

N-[[2-(4-Chlorophenyl)-1,2,3,3a,7,7a-hexahydro-4,7-epoxy-4H-isoindol-4-yl]methyl]-2-nitrobenzenesulfonamide21-26 197

(3aα,4β,7β,7aα)-Hexahydro-2-[(1S)-1-epoxy-1H-isoindole-1,3(2H)-dione.  8198

(3aα,4β,7β,7aα)-Hexahydro-2-[(1S)-2-hydroxy-1-phenylethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione. 8 199

(3aα,4β,7β,7aα)-2-[(1S)-2-(Acetyloxy)-1-phenylethyl]-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione. 8 200

(3aα,4α,7α,7aα)-3a,4,7,7a-Tetrahydro-2-[(1S)-1-phenylethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione. 8 201

(3aα,4β,7β,7aα)-Hexahydro-2-[(1R)-1-phenylethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione. 8 202

(3aα,4β,7β,7aα)-4-[[[(Octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)methyl]amino]benzoicacid.  8 203

(3aα,4β,7β,7aα)-Hexahydro-2-(4-morpholinylmethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione. 8

EXAMPLE 204(3aα,4β,7β,7aα)-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(204D/25B)

A. 2-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-5-methylfuran(204A)

To a solution of compound 21A (2.00 g, 15.9 mmol) in DMF (50 mL) wasadded imidazole (1.62 g, 23.9 mmol), followed by tert-butyldimethylsilylchloride (2.63 g, 17.5 mmol). After 2 h at 25° C., the reaction waspoured into diethyl ether (300 mL) and washed with water (1×100 mL), 1 NHCl (1×100 mL), water (1×100 mL), brine (1×50 mL) and dried overanhydrous MgSO₄. Crude compound 204A was analyzed by LCMS and NMR anddetermined to be pure enough to be carried on directly to the next step.HPLC: 100% at 4.347 min (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA,4 mL/min, monitoring at 220 nm).

B.(3aα,4β,7β,7aα)-4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]-oxy]ethyl]hexahydro-7-methyl-4,7-epoxy-1H-isobenzofuran-1,3(2H)-dione(204B)

Compound 204A (4.0 g, 18.9 mmol) and maleic anhydride (1.42 g, 14.5mmol) were dissolved in dichloroethane (10 mL) and stirred at 25° C. for60 hours. The volatiles were then removed in vacuo and the resultingorange oil was dissolved in absolute ethanol (50 mL) and 10% Pd/C (1.00g, cat.) was added. Hydrogen was then introduced via a balloon. After 3h, the reaction was filtered through Celite rinsing with EtOAc andconcentrated in vacuo. The crude anhydride was purified by rapid flashchromatography on SiO₂ eluting with acetone/chloroform (0-2-4% acetone)to give 1.30 g (3.82 mmol, 20%) of compound 204B as a clear oil, inaddition to 3.00 g (12.5 mmol, 66%) of the starting compound 204A.Characterization by proton NMR spectroscopy showed only the exo isomer.¹H NMR (400 MHz, CDCl₃) δ=3.83 (2H, t, J=6.0 Hz), 3.22 (1H, d, J=8.2Hz), 3.06 (1H, d, J=8.2 Hz), 1.70-2.25 (6H, m), 1.55 (3H, s), 0.82 (9H,s), 0.00 (6H, s).

C.(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]-oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(204C)

Compound 204B (0.250 g, 0.734 mmol) and4-amino-2-trifluoromethylbenzonitrile (0.124 g, 0.668 mmol) weresuspended in dry toluene (2.0 mL) in a sealed tube. MgSO₄ (0.200 g) andtriethylamine (0.5 mL) were then added and the tube was sealed andplaced in a oil bath at 125° C. After 40 h, the reaction was cooled to25° C., filtered and concentrated in vacuo. The crude material waspurified by flash chromatography on SiO₂ eluting with CH₂Cl₂ to give0.111 g (0.281 mmol, 30%) of compound 204C as a yellow solid. HPLC: 92%at 4.203 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min,monitoring at 220 nm). MS (ESI): m/z 531.1 [M+Na]⁺.

D.(3aα,4β,7β,7aα)-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(204D)

Compound 204C (0.031 g, 0.061 mmol) was dissolved in THF (0.5 mL) andtransferred to a polypropylene container followed by cooling to 0° C.HF.pyridine (˜47% HF, 0.1 mL) was then added. After 15 min, the reactionwas complete as determined by LC and was poured into cold sat. aqueousNaHCO₃. The mixture was extracted with CH₂Cl₂ (3×10 mL). The combinedorganic layers were washed with 1 N HCl (1×20 mL) and dried overanhydrous Na₂SO₄. Compound 204D was isolated as a yellow oil andcompared to the material prepared in Example 25. No purification wasnecessary.

EXAMPLE 205 (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(phenylmethyl)-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(205Ci and 205Cii, respectively)

A. 2-Methyl-5-(phenylmethyl)-furan (205A)

n-BuLi (1.8 mL, 4.51 mmol, 2.5 M in hexane) was added to a solution of2-methylfuran (0.37 mL, 4.10 mmol) in anhydrous THF (3 mL) at −25° C.The resulting solution was stirred at room temperature for 3 h and thencooled to −15° C. Benzyl bromide (0.59 mL, 4.92 mmol), which was passedthrough a plug of aluminum oxide, was added and the solution was warmedto rt and stirred overnight. Saturated NH₄Cl solution (5 mL) was addedand the mixture was stirred for 1 h. The reaction mixture was thenextracted with ether (2×5 mL) and the combined organic extracts weredried and concentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with hexanes gave 323 mg (1.88mmol, 46%) of compound 205A as colorless oil. HPLC: 95% at 3.72 min(retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm) and about 400 mg mixture of product and benzyl bromide (˜2:1 byHPLC).

B. (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(phenylmethyl)-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(205Bi and 205Bii, respectively)

A solution of compound 205A (124 mg, 0.72 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(290 mg, 1.09 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature.After 4 days, the reaction mixture was concentrated under reducedpressure. Purification by flash chromatography on silica gel elutingwith CH₂Cl₂ gave 62 mg (0.14 mmol, 20%) of a mixture of compounds 205Biand 205Bii as a white solid, which was used directly in the next step.HPLC: 93% at 3.69 min (retention time) (YMC S5 ODS column 4.6×50 mm,10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm).

C. (3aα,4β,7β,7aα)- and(3aα,4α,7α,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(phenylmethyl)-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)-benzonitrile(205Ci and 205Cii, respectively)

A solution of a mixture of compounds 205Bi and 205Bii (62 mg, 0.14 mmol)and 10% Pd/C (12 mg, cat.) in EtOH (3.5 mL) was stirred under a hydrogenatmosphere at room temperature for 2 h. The reaction mixture wasfiltered through Celite and concentrated under reduced pressure.Purification by flash chromatography on silica gel eluting with 35%EtOAc/hexanes gave 22 mg (0.05 mmol, 35%) of compound 205Ci and 12 mg(0.027 mmols, 19%) of compound 205Cii. Compound 205Ci: HPLC: 98% at 3.75min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ESI): m/z 458.2 [M+NH₄]⁺. Compound 205Cii:HPLC: 97% at 3.78 min (retention time) (YMC S5 ODS column 4.6×50 mm,10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm). MS (ESI): m/z 473.45 [M+CH₃OH]⁺.

EXAMPLE 206(3aα,4β,7β,7aα)-2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-propanenitrile(206)

A solution of compound 36 (34 mg, 0.074 mmol) and NaCN (24 mg, 0.49mmol) in DMSO (1 mL) was heated at 100° C. for 0.5 h. After cooling, thereaction mixture was poured into H₂O (5 mL) and the aqueous layer wasextracted with EtOAc (2×5 mL). The combined organic layers were washedwith H₂O (2×5 mL), dried over Na₂SO₄ and concentrated under reducedpressure. Purification by flash chromatography on SiO₂ eluting with 50%EtOAc/hexanes followed by reverse phase preparative HPLC [30.41 min(retention time) (YMC S5 ODS 30×250 mm, 10-90% aqueous methanol over 30minutes containing 0.1% TFA, 25 mL/min, monitoring at 220 nm)] gave 6.6mg (0.016 mmol, 22%) of compound 206 as a white solid. HPLC: 99% at 2.89min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 402.1 [M−H]⁻.

EXAMPLE 207(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-7-[2-(4-morpholinyl)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile,trifluoroacetate (1:1) (207)

A solution of compound 36 (15.6 mg, 0.0341 mmol) and morpholine (6.0 μL,0.068 mmol) in toluene (1 mL) was heated at 100° C. overnight. Aftercooling, the reaction mixture was concentrated under reduced pressure.Purification by flash chromatography on SiO₂ eluting with 10%MeOH/CH₂Cl₂ followed by reverse phase preparative HPLC [23.96 min(retention time) (YMC S5 ODS 30×250 mm, 10-90% aqueous methanol over 30minutes containing 0.1% TFA, 25 mL/min, monitoring at 220 nm)] gave 8.7mg (0.015 mmol, 44%) of compound 207 (TFA salt) as a white solid. HPLC:99% at 2.02 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 464.3 [M+H]⁺.

EXAMPLE 208(3aα,4β,7β,7aα)-2-(5-Fluoro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(208C)

A. 1-Fluoro-5-nitronaphthalene (208A)

To a solution of 6 N HCl (12 mL) was added 1.47 g (7.83 mmol) of finelypowdered 5-nitro-1-naphthylamine, as described in J. Chem. Soc. 1187(1949). The mixture was cooled to 0° C. and a cold solution of NaNO₂(547 mg, 7.93 mmol) in 2 mL H₂O was added slowly so that the temperaturewas kept near 0° C. After the addition was complete, the reactionmixture was stirred for 30 min and filtered. The filtrate was cooled to0° C. and treated with cold 4.5 M NaBF₄ solution (5 mL) to give completeprecipitation of the diazonium borofluoride. The mixture was kept at 0°C. for 30 min before it was filtered and the precipitates were washedwith cold 4.5 M NaBF₄ solution (5 mL), ice-cold ethanol (10 mL) and Et₂O(20 mL). The obtained solids were air dried to yield 1.74 g (77%) of thecorresponding diazonium salt.

To 1.70 g (5.92 mmol) of the above diazonium borofluoride was added 5 gof sand and the components were thoroughly mixed. The reaction mixturewas heated cautiously under reduced pressure until decomposition set in.Toward the end of the reaction the flask was further heated for 30 minto 130° C. to assure complete conversion. After cooling the reactionmixture was dissolved in acetone and the contents were preabsorbed onsilica gel. Purification was achieved by flash chromatography on silicagel, eluting with 0 to 10% EtOAc in hexanes to give 449 mg (2.35 mmol,40%) of compound 208A as a white solid.

B. 1-Amino-5-fluoronaphthalene (208B)

A solution of compound 208A (62 mg, 0.32 mmol) in 1 mL EtOH containing0.1 mL 12 N HCl was heated to reflux. Iron powder (62 mg, 1.11 mmol) wasadded in small portions and heating was continued for 2 h. The mixturewas cooled, neutralized with 1 N NaOH solution and the aqueous layer wasextracted with CH₂Cl₂. The combined organic phases were dried over MgSO₄and concentrated in vacuo to leave a residue which was purified by flashchromatography on silica gel eluting with 40 to 80% EtOAc in hexanes togive 42 mg (0.26 mmol, 80%) of compound 208B as a yellow solid.

C.(3aα,4β,7β,7aα)-2-(5-Fluoro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(208C)

Compound 208B (42 mg, 0.26 mmol), compound 20A (54 mg, 0.27 mmol), MgSO₄(69 mg, 0.58 mmol) and triethylamine (191 μL, 1.37 mmol) were taken upin 2 mL of toluene and placed in a sealed tube. The sealed tube washeated at 135° C. for 14 h. The cooled reaction mixture was filteredthrough a short pad of Celite eluting with CH₂Cl₂ and the solvent wasremoved under reduced pressure. The residue was purified by reversephase preparative HPLC (YMC S5 ODS 20×100 mm eluting with 30-100%aqueous methanol over 10 mincontaining 0.1% TFA, 20 mL/min) to give 15mg (0.044 mmol, 17%) of compound 208C as a light yellow solid. HPLC: 16%at 2.96 min & 77% at 3.06 min (atropisomers, retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 340.2 [M+H]⁺.

EXAMPLE 209(3aα,4β,7β,7aα)-2-(5-Fluoro-4-nitro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(209C)

A. N-(5-Fluoro-1-naphthalenyl)acetamide (209A)

A solution of 141 mg (0.74 mmol) of compound 208A in 2 mL of AcOH washeated to reflux and treated with small portions of iron powder (118 mg,2.11 mmol). The mixture was kept at reflux for 15 min before 73 μL (0.78mmol) of Ac₂O was added. After an additional 15 min at reflux, themixture was cooled and filtered eluting with CH₂Cl₂. The filtrate wasthen concentrated under reduced pressure and the residue was purified byflash chromatography on silica gel eluting with 20 to 50% EtOAc in togive 145 mg (0.71 mmol, 97%) of compound 209A as a white solid.

B. 1-Amino-5-fluoro-4-nitronaphthalene (209B)

Compound 209A (133 mg, 0.645 mmol) was dissolved in 1 mL AcOH and theresulting solution was cooled to 10° C. At this temperature, 80.0 μL(2.00 mmol) of red fuming HNO₃ was added and stirring was continued for15 min before the reaction was quenched by the addition of crushed ice.The aqueous layer was extracted with CH₂Cl₂ and the combined organicphases were dried over MgSO₄ and concentrated in vacuo. The resultingresidue was dissolved in 3 mL EtOH, heated to reflux and treated with0.5 mL of 40% aqueous NaOH solution. Stirring was continued for 15 minbefore the reaction was cooled and diluted with H₂O. The aqueous layerwas extracted with CH₂Cl₂ and the combined organic phases were driedover MgSO₄ and concentrated in vacuo. The resulting residue was purifiedby flash chromatography on silica gel, eluting with 40 to 70% EtOAc inhexane to afford 36 mg (0.17 mmol, 27%) of compound 209B as a yellowsolid.

C.3aα,4β,7β,7aα)-2-(5-Fluoro-4-nitro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(209C)

Compound 209B (36 mg, 0.18 mmol) was reacted in a sealed tube withcompound 20A (38 mg, 0.19 mmol), MgSO₄ (46 mg, 0.39 mmol) and Et₃N (128μL, 0.920 mmol) in 250 μL toluene according to the above proceduredescribed in example 208C to give, after purification by reverse phasepreparative HPLC (YMC S5 ODS 20×100 mm eluting with 30-100% aqueousmethanol over 10 mincontaining 0.1% TFA, 20 mL/min), 27 mg (0.070 mmol,39%) of compound 209C as a yellow solid. HPLC: 8% at 2.88 min & 84% at3.06 min (atropisomers, retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 402.0[M+H]⁺.

EXAMPLE 210(3aα,4β,7β,7aα)-2-(1,1-Dioxidobenzo[b]thiophen-3-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(210)

mCPBA (160 mg, 0.641 mmol, 70% pure) was added to a solution of compound134 (70.0 mg, 0.214 mmol) in CH₂CL₂ (2 mL) at rt. After the startingmaterial was consumed, the reaction was quenched with sat. NaHCO₃, andextracted with CH₂Cl₂. The organic layer was washed with 1 N NaOH, driedover Na₂SO₄ and concentrated under reduced pressure to give 63.9 mg(0.178 mmol, 83%) of compound 210 as a white solid. HPLC: 99% at 3.81min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 360.0 [M+H]⁺.

EXAMPLE 2114-(1,3,3a,4,7,7a-Hexahydro-4,6,7-trimethyl-1,3-dioxo-4,7-epoxy-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-(trifluoromethyl)benzonitrile(211)

2,4,5-Trimethyl oxazole (0.48 mL, 4.14 mmol) was dissolved in toluene(2.0 mL) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(1.00 g, 3.76 mmol) was added. The reaction mixture was stirred at 75°C. under nitrogen for 2.5 hrs. The solution was cooled to roomtemperature and the resulting precipitate was filtered and rinsed withtoluene to give 0.51 g (35%) of compound 211 as a light grey solid. NMRanalysis revelaed that compound 211 was one isomer (exo/endo) howeverthe identity of the isomer could not be determined by NMR analysis.HPLC: 100% at 2.85 min (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA,4 mL/min, monitoring at 220 nm). MS (ES): m/z 378.42 [M+H]⁺.

EXAMPLE 212(3aα,4β,7β,7aα)-Tetrahydro-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3,5(2H,4H)-trione&(3aα,4α,7α,7aα)-Tetrahydro-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3,5(2H,4H)-trione(212i & 212ii, respectively)

2,2-Dimethyl-3(H)-furanone (0.500 g, 4.46 mmol) and1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (1.07 g, 4.46 mmol,prepared as described in Example 1B) were suspended in toluene (20 mL)in a sealed tube. The mixture was heated at 110° C. for 4 h and thencooled to 25° C. followed by concentration in vacuo. The resultingresidue was purified by flash chromatography on SiO₂ eluting withmethylene chloride to yield 0.411 g (26%) of compound 212i as a whitesolid and 0.193 g (12%) of compound 212ii as a white solid. Thestructural assignments were confirmed by 1-D NOE proton NMR experiments.Compound 212i: HPLC: 100% at 2.817 min (retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 376.0[M+Na]⁺. Compound 212ii: HPLC: 100% at 3.013 min (retention time) (YMCS5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ES): m/z 354.02 [M+H]⁺.

EXAMPLE 213(3aα,4β,7β,7aα)-2-(5-Chloro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(213B)

A. 1-Amino-5-chloronaphthalene (213A)

To a solution of 1.74 g (6.06 mmol) of the diazonium borofluoride(described in Example 208A) in acetone (7 mL) was added 693 mg (7.00mmol) of CuCl in small portions. After the evolution of nitrogen hadceased the acetone was removed under reduced pressure and the residuewas taken up in CH₂Cl₂ (30 mL). The organic phase was washed with H₂O(30 mL), dried over MgSO₄, concentrated in vacuo and finally purified byflash chromatography (silica gel, EtOAc in hexane 0 to 15%) to give 754mg (70%) of 1-chloro-5-nitronaphthalene.

The above synthesized 1-chloro-5-nitronaphthalene (540 mg, 2.6 mmol) wasdissolved in 10 mL AcOH, followed by treatment with 415 mg (7.43 mmol)iron powder and subsequently acylated with Ac₂O (0.26 mL, 2.73 mmol)according to the procedure described in Example 209A to give 543 mg(95%) of 1-acetamino-5-chloronaphthalene.

A solution of the above synthesized 1-acetamino-5-chloronaphthalene (52mg, 0.24 mmol) in 3 mL EtOH was heated to reflux and treated with 0.5 mL40% aqueous NaOH solution. The mixture was refluxed until no morestarting material could be detected, cooled and concentrated underreduced pressure. The residue was taken up in CH₂Cl₂ (50 mL) and waswashed with H₂O (25 mL). The organic layer was dried over MgSO₄ andconcentrated in vacuo to leave 41 mg (98%) of compound 213A as a whitesolid.

B.(3aα,4β,7β,7aα)-2-(5-Chloro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(213B)

Compound 213A (24 mg, 0.14 mmol) was reacted in a sealed tube withcompound 20A (29 mg, 0.15 mmol), MgSO₄ (36 mg, 0.30 mmol) and Et₃N (100μL, 0.710 mmol) in 250 μL toluene according to the procedure describedin Example 208C to give, after purification by reverse phase preparativeHPLC (YMC S5 ODS 20×100 mm eluting with 30-100% aqueous methanol over 10mincontaining 0.1% TFA, 20 mL/min), 27 mg (40%) of compound 213B as awhite solid. HPLC: 98% at 1.82 min (retention time) (YMC S5 TurboPackPro column 4.6×33 mm eluting with 10-90% aqueous methanol over 2 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 356.4 [M+H]⁺.

EXAMPLE 214(3aα,4β,7β,7aα)-2-(5-Chloro-4-nitro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(214B)

A. 1-Amino-5-chloro-4-nitronaphthalene (214A)

1-Acetamino-5-chloronaphthalene (150 mg, 0.68 mmol, prepared asdescribed in Example 213A) was dissolved in 1 mL AcOH and treated with82 μL of red fuming HNO₃ and subsequently deacylated with 1 mL 40%aqueous NaOH solution in 3 mL EtOH according to the procedure describedin Example 209A to yield 49 mg (32%) of compound 214A as a yellow solid.

B.(3aα,4β,7β,7aα)-2-(5-Chloro-4-nitro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(214B)

Compound 214A (27 mg, 0.12 mmol) was reacted in a sealed tube withcompound 20A (26 mg, 0.13 mmol), MgSO₄ (32 mg, 0.27 mmol) and Et₃N (88μL, 0.63 mmol) in 250 μL toluene according to the procedure described inExample 208C to give, after purification by reverse phase preparativeHPLC (YMC S5 ODS 20×100 mm eluting with 30-100% aqueous methanol over 10mincontaining 0.1% TFA, 20 mL/min) 22 mg (45%) of compound 214B as ayellow solid. HPLC: 24% at 3.06 min & 76% at 3.25 min (atropisomers,retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 418.0 [M+NH₄]⁺.

EXAMPLE 215(3aα,4β,7β,7aα)-4-Ethylhexahydro-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(215B)

A.(3aα,4β,7β,7aα)-4-Ethylhexahydro-7-methyl-4,7-epoxyisobenzofuran-1,3-dione(215A)

2-Ethyl-5-methylfuran (1.89 mL, 15.3 mmol) was dissolved in methylenechloride (10 mL) and maleic anhydride (1.00 g, 10.2 mmol) was added. Thereaction was stirred at 25° C. for 18 h and then concentrated in vacuo.The resulting crude bicycle was dissolved in EtOAc (50 mL) and 10% Pd/C(0.40 g) was added. Hydrogen was then introduced via a balloon. After 4h, the reaction was filtered through Celite, rinsing with EtOAc.Concentration in vacuo gave the crude compound 215A (1.93 g) as a whitesolid. This material was taken on directly to the next reaction withoutpurification.

B.(3aα,4β,7β,7aα)-4-Ethylhexahydro-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(215B)

Compound 215A (0.168 g, 0.798 mmol) and 1-amino-4-nitronaphthalene (0.10g, 0.53 mmol) were suspended in toluene (0.8 mL) and TEA (0.2 mL) andmagnesium sulfate (0.1 g) were added. The mixture was heated at 135° C.in a sealed tube for 18 h. The reaction was then cooled to rt andfiltered, rinsing with chloroform. Concentration gave the crude productwhich was purified by preparative TLC on SiO₂ eluting with methylenechloride. This gave 0.077 g (0.20 mmol, 38%) of compound 215B as ayellow solid. HPLC: 100% at 3.260 min (retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 381.05 [M+H]⁺.

EXAMPLE 216(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)-N-(4-fluorophenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-acetamide(216B)

A. N-(4-Fluorophenyl)-5-methyl-2-furanacetamide (216A)

5-Methyl-2-furanacetic acid (1.00 g, 7.14 mmol, synthesized as describedWO 9507893, Example 19) was dissolved in CH₃CN/DMF (4:1, 25 mL),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.37 g, 7.14 mmol) and1-hydroxy-7-azabenzotriazole (0.972 g, 7.14 mmol) were then addedfollowed by 4-fluoroaniline (0.676 mL, 7.14 mmol). After 3 h, thereaction was diluted with EtOAc (150 mL) and washed with 1 N HCl (1×30mL), sat. aq. NaHCO₃ (1×30 mL), brine (1×40 mL) and dried over sodiumsulfate. Compound 216A (1.58 g, 95%)) was isolated as a yellow foamafter concentration in vacuo. No further purification was necessary.HPLC: 78% at 2.647 min (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm).

B.3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)-N-(4-fluorophenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-acetamide(216B)

Compound 216A (0.200 g, 0.858 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(0.164 g, 0.616 mmol) were dissolved in benzene and heated at 60° C. for14 h. The reaction was then cooled and concentrated in vacuo. Theresulting orange oil was dissolved in EtOAc (15 mL) and 10% Pd/C (0.050g) was added. Hydrogen was then introduced via a balloon. After 3 h, thereaction was filtered through Celite rinsing with EtOAc and concentratedin vacuo. The resulting crude material was purified by preparative TLCon silica eluting with 5% acetone in methylene chloride to give 0.166 g(54%) of compound 216B as a white solid. NMR spectroscopy showed only asingle isomer which was determined to be exo by NOE experiments. HPLC:95% at 3.200 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 484.0 [M+H]⁺.

EXAMPLE 217(3aα,4β,7β,7aα)-Hexahydro-4-methyl-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione,faster eluting enantiomer &(3aα,4β,7β,7aα)-Hexahydro-4-methyl-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione,slower eluting enantiomer (217i & 217ii, respectively)

Racemic compound 137 was separated into the individual antipodes bychiral reverse phase liquid chromatography. A Chiralpak AD-R column(4.6×250 mm) was used eluting with 70% acetonitrile/30% water at 1mL/min. UV detection at 220 nm was used. The faster eluting isomer,compound 217i (retention time=15.66 min), was found to be 99.9% ee andthe slower eluting isomer, compound 217ii (retention time=15.66 min) was99.6% ee by analytical chiral reverse phase chromatography.

EXAMPLE 218(3aα,4β,7β,7aα)-4-[4-[2-[[(4-Fluorophenyl)methyl]methylamino]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(218B)

A. (4-Fluorobenzyl)methylamine & Bis(4-fluorobenzyl)methylamine (218A &218A′)

Compounds 218A & 218A′ were made in accordance with the proceduredescribed by Singer et al. J. Med. Chem. 29, 40-44 (1986).4-Fluorobenzyl bromide (189 mg, 1.00 mmol) was refluxed in a solution ofethanol (1.5 mL) and methylamine (5 mL, 2 M solution in MeOH) for 3 h.An additional portion of methylamine (2 mL) was added and the mixturewas refluxed for an additional hour. The solution was cooled andconcentrated in vacuo, and the residue was dissolved in a mixture of 2 NHCl (3 mL) and ether (1.5 mL). The layers were separated and the aqueouslayer was extracted with an additional portion of ether. The aqueoussolution was chilled to 0° C., titrated to pH 11 with NaOH and extractedwith CH₂Cl₂. The extracts were dried over MgSO₄ and concentrated invacuo to give 120 mg of a 2.5:1 mixture of compounds 218A and compound218A′ respectively. The crude mixture was taken on without furtherpurification.

B.(3aα,4β,7β,7aα)-4-[4-[2-[[(4-Fluorophenyl)methyl]-methylamino]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(218B)

A solution of compound 36 (34.3 mg, 0.075 mmol) and compounds 218A &218A′ (21 mg, ˜0.088 mmol (of 218A)) in toluene (0.4 mL) was heated at100° C. overnight. The reaction mixture was cooled to room temperatureand then concentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with 25% acetone/75% CH₂Cl₂ gave 30mg (0.058 mmol, 78%) of 218B as a yellow solid. HPLC: 99% at 2.46 min(retention time) (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, monitoring at 220 nm). MS (ES):m/z 516.26 [M+H]⁺.

EXAMPLE 219(3aα,4β,5β,6β,7β,7aα)-4-(Octahydro-4,5,6,7-tetramethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(219D)

A. 2,3,4,5-Tetramethylfuran (219A)

Compound 219A was made in accordance with the procedures described inHancock et al. J. Org. Chem. 42, 1850-1856 (1977) & Amarnath et al. J.Org. Chem., 60, 301-307 (1995). 2-Propanone (100 mL, 1.1 mol) wasrefluxed over PbO₂ (26.7 g, 0.112 mol) for 28 h. After cooling to rt,the reaction mixture was filtered and the residue was washed withacetone. The filtrate was concentrated under reduced pressure to removethe acetone and then distilled at 20 Torr. The fraction that came overbetween 100-120° C. was collected to give 6.75 g (42.5%) of3,4-dimethylhexane-2,5-dione as a light yellow oil.

A solution of 3,4-dimethylhexane-2,5-dione (3.00 g, 21.1 mmol) andp-toluenesulfonic acid (401 mg, 2.11 mmol) in benzene (30,mL) was heatedto reflux in a Dean-Stark trap overnight. The reaction mixture wasdistilled at atmospheric pressure to remove the excess benzene. Theremaining mixture was transferred to a smaller flask and distilled atatmospheric pressure. The fraction that came over between 80-100° C. wascollected to give 509 mg (19%) of compound 219A as a light yellow oil.

B.(3aα,4β,7β,7aα)-4-Ethyl-3a,4,7,7a-tetrahydro-4,5,6,7-tetramethyl-4,7-epoxyisobenzofuran-1,3-dione(219B)

A solution of compound 219A (400 mg, 3.22 mmol) and maleic anhydride(442 mg, 4.51 mmol) in Et₂O (1.5 mL) was stirred at rt overnight. Thereaction mixture was then placed in freezer for 5 days, after which timethe resulting crystals were collected and dried to give 0.26 g (37%) ofcompound 219B as tan crystals. The crude compound 219B was taken on tothe next step without further purification.

C.(3aα,4β,5α,6α,7β,7aα)-4-Ethylhexahydro-4,5,6,7-tetramethyl-4,7-epoxyisobenzofuran-1,3-dione(219C)

A solution of compound 219B (120 mg, 0.545 mmol) and 10% Pd/C (24 mg,cat.) in EtOAc (2 mL) was stirred under a balloon of hydrogen at roomtemperature overnight. The reaction mixture was filtered through Celiteand concentrated under reduced pressure to give 100 mg (0.446 mmol, 82%)of compound 219C as a white solid, which was carried on with no furtherpurification.

D.(3aα,4β,5β,6β,7β,7aα)-4-(Octahydro-4,5,6,7-tetramethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(219D)

A solution of compound 219C (44.4 mg, 0.2 mmol),5-amino-2-cyanobenzotrifluoride (45 mg, 0.24 mmol), TEA (0.04 mL) andMgSO₄ (20 mg) in toluene (0.2 mL) was heated at 135° C. overnight. Thereaction mixture was cooled to room temperature, filtered and thenconcentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with 40% EtOAc/hexanes followed bywashing the resulting solid with MeOH gave 17 mg (0.043 mmol, 22%) ofcompound 219D as a white solid. HPLC: 90% at 3.11 min (retention time)(YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, monitoring at 220 nm). MS (ES): m/z 391.2 [M−H]⁻.

EXAMPLE 220(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile,faster eluting antipode &(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile,slower eluting enantiomer (220i & 220ii, respectively)

Racemic compound 35 was separated into the individual antipodes bychiral normal phase liquid chromatography. A Chiralpak AD column (50×500mm) was used eluting with 85% hexanes/7.5% methanol/7.5% ethanol, at 50mL/min. UV detection at 220 nm was used. The faster eluting isomercompound 220i (retention time=55.86 min) was found to have 95.8% ee([α]_(D) ²⁵=−53.02°, C=3.134 mg/cc in CH₂Cl₂) and the slower elutingisomer compound 220ii (retention time=62.86 min) was 86% ee([α]D²⁵=+48.740, C=2.242 mg/cc in CH₂Cl₂) by analytical chiral normalphase chromatography.

EXAMPLE 221(3aα,4β,5β,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo=4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(221B)

A.(3aα,4β,7β,7aα)-4-(hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(221Ai) &(3aα,4α,7α,7aα)-4-(hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(221Aii)

A solution of 2,5-dimethylfuran (0.800 mL, 7.51 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(synthesized as described in Example 1B, using4-cyano-3-trifluoromethylaniline in place of 4-bromo-3-methylaniline)(1.00 g, 3.75 mmol) in benzene (4 mL) was heated at 60° C. overnight.The reaction mixture was concentrated under reduced pressure and placedon a high vacuum pump until the oil solidified to give a 3:1 mixture(determined by LC and NMR) of compounds 221Ai & 221Aii, respectively, asa brown solid, which was used directly in the next step without furtherpurification.

B.(3aα,4β,5β,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(221B)

BH₃.THF (3.75 mL, 3.75 mmol, 1M in THF) was added to a solution of crudecompounds 221Ai & 221Aii (3.75 mmol) in THF (12.5 mL) at 0° C. After thestarting material was consumed the reaction mixture was concentratedunder reduced pressure. The resulting residue was then dissolved intoluene (12.5 mL), Me₃NO (845 mg, 11.2 mmol) was added and the mixturewas heated to reflux overnight. The reaction mixture was then cooled tort, added to H₂O and extracted with EtOAc (3×). The combined organiclayers were dried over MgSO₄ and concentrated under reduced pressure.Purification by flash chromatography on SiO₂ eluting with 75%EtOAc/hexanes gave 0.354 g (25%) of compound 221B as a tan powder. HPLC:90% at 2.45 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 381.11 [M+H]⁺.

EXAMPLE 222(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(222D)

A. 3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2,5-dimethylfuran (222A)

2,5-Dimethyl-3(3H)-furanone (2.00 g, 17.8 mmol) was dissolved inmethylene chloride (180 mL). TEA (7.43 mL, 53.5 mmol) was added followedby TBSOTf (4.92 mL, 21.4 mmol) at 25° C. After 1 h, the reaction wasconcentrated in vacuo and the resulting slurry was run through a silicagel column conditioned with 3% TEA in hexanes. The product was elutedwith 3% TEA/hexanes to give 3.6 g (89%) of compound 222A as an orangeoil which was used directly in subsequent reactions.

B.(3aα,4β,7β,7aα)-4-[5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1,3,3a,4,7,7a-hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(222B)

4-(2,5-Dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(1.00 g, 3.85 mmol) was dissolved in benzene (5.0 mL) and the compound222A (1.30 g, 5.77 mmol) was added. The reaction mixture was warmed to60° C. for 2 h and then cooled to 25° C. The solution was thenconcentrated in vacuo to give compound 222B as a yellow oil which wascarried on to the next reaction without purification. HPLC: 60% at 4.013min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

C.(3aα,4β,5α,7β,7aα)-4-[5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(222C)

Crude compound 222B (3.85 mmol) was dissolved in ethyl acetate (75 mL)and 10% Pd/C (1.20 g) was added. Hydrogen was then introduced via aballoon. After 24 h, the reaction was filtered through Celite rinsingwith ethyl acetate and concentrated in vacuo to give a yellow oil. Thecrude product was purified by flash chromatography on silica gel elutingwith methylene chloride/acetone (0%-1%-2% acetone) to give 0.710 g (35%)compound 222C as a yellow solid. HPLC: 100% at 4.160 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). MS (ES): m/z 517.6 [M+Na]⁺.

D.(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(222D)

Compound 222C (0.040 g, 0.081 mmol) was dissolved in THF (1.0 mL) andHFoPyridine (0.5 mL) was added. After 2 h, the reaction was carefullypoured into cold saturated aq. NaHCO₃. The mixture was then extractedwith methylene chloride (3×10 mL). The combined organics were washedwith 1 N HCl (1×10 mL) and dried over anhydrous sodium sulfate.Concentration in vacuo gave 0.031 g (10%) compound 222D as a yellowsolid. NOE experiments confirmed the assigned isomer. HPLC: 98% at 2.777min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 403.06 [M+Na]⁺.

EXAMPLE 223 (αR)-α-Methoxybenzeneacetic acid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester (223C)

A.(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(223A)

A solution of 4-amino-1-naphthalenecarbonitrile (19.2 g, 114 mmol) andmaleic anhydride (14.0 g, 113 mmol) in AcOH (230 mL) was heated at 115°C. for 12 h. After cooling to rt, the reaction mixture was concentratedunder reduced pressure then diluted with CH₂Cl₂ (2.5 L). The organiclayer was washed 3× with H₂O (3 L), 1× with sat. aq. Na₂CO₃ (1 L) and 1×with brine (1 L), dried over MgSO₄ and concentrated to ˜200 mL underreduced pressure. Purification by flash chromatography on cationexchange resin (60 g, CUBX13M6 from United Chemical Technologies)eluting with CH₂Cl₂ gave 25.0 g (88%) of4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile as a yellowsolid. HPLC: 96% at 2.48 min (retention time) (Phenomenex-prime S5-C18column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 249.25[M+H]⁺.

4-(2,5-Dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (1.00 g,4.03 mmol) was suspended in benzene (6.0 mL) in a sealed tube andcompound 204A (1.11 g, 5.24 mmol) was added. The reaction was heated at60° C. for 16 h and then cooled to 25° C. The benzene was removed invacuo to give a yellow solid. The solid was dissolved in ethyl acetate(40 mL) and Pd/C (10% Pd, 0.300 g) was added. Hydrogen was thenintroduced via a balloon. After 4 h, the reaction was filtered throughCelite rinsing with ethyl acetate. Concentration in vacuo gave a paleyellow solid which was purified by flash chromatography on silica geleluting with acetone/chloroform (0%-1.5%-3% acetone) to give 1.53 g(77%) compound 223A as a yellow foam. HPLC: 86% at 4.173 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm).

B.(3aα,4β,7β,7aα)-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(223B)

Compound 223A (1.37 g, 2.97 mmol) was dissolved in THF (8.0 mL) andtransferred to a polypropylene bottle and cooled to 0° C. HFoPyridine(2.0 mL) was then added. After 20 min, the reaction was carefully pouredinto cold sat. aq. sodium bicarbonate and extracted with methylenechloride (3×30 mL). The organics were then washed with 1 N HCl and driedover anhydrous sodium sulfate. Concentration in vacuo gave 0.99 g (89%)the compound 223B as a yellow foam which was not purified further. HPLC:96% at 2.443 and 2.597 min (atropisomers, retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 399.02 [M+Na]⁺.

C. (αR)-α-Methoxybenzeneacetic acid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester (223C)

Compound 223B (0.200 g, 0.575 mmol) was added to a solution of WSDCC(0.138 g, 0.719 mmol) and (R)-mandelic acid (0.096 g, 0.57 mmol) indichloromethane (6.0 mL). 4-DMAP (0.005 g) was then added and thereaction was stirred at 25° C. for 4 h. The mixture was then dilutedwith dichloromethane, washed with 1 N HCl (2×10 mL) followed by sodiumbicarbonate (1×10 mL) and dried over anhydrous sodium sulfate.Concentration in vacuo gave 0.220 g (71%) compound 223C as a yellowsolid which was not purified further. HPLC: 100% at 3.283 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). MS (ES): m/z 547.26 [M+Na]⁺.

EXAMPLE 224(3aα,4β,7β,7aα)-2-(Methylthio)-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile(224)

4-Amino-2-(methylthio)benzonitrile (100 mg, 0.609 mmol, synthesized asdescribed in EP 40931 A1) was reacted in a sealed tube with compound 20A(131 mg, 0.668 mmol), MgSO₄ (161 mg, 1.34 mmol) and Et₃N (0.440 mL, 3.17mmol) in 0.50 mL toluene according to the procedure described in Example208C to give, after purification by reverse phase preparative HPLC (YMCS5 ODS 20×100 mm eluting with 30-100% aqueous methanol over 10mincontaining 0.1% TFA, 20 mL/min), 137 mg (0.400 mmol, 66%) of compound224 as a white solid. HPLC: 100% at 2.73 min (retention time) (YMC S5ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 401.0 [M−H+OAc]⁻.

EXAMPLE 225(3aα,4β,7β,7aα)-2-(Methylsulfinyl)-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile(225)

To an ice-cold suspension of compound 224 (30 mg, 0.088 mmol) in 2 mL ofH₂O/MeOH (1:1) was added oxone (80 mg, 0.26 mmol) in one solid portion.The resulting mixture was stirred for 4 h at 0° C. before it was dilutedwith H₂O (10 mL) and extracted with CH₂Cl₂ (2×20 mL). The combinedorganic layers were dried and concentrated in vacuo to leave a residuewhich was purified by filtering the material through a short pad ofsilica gel eluting with CH₂Cl₂ to yield 32 mg (0.088 mmol, 100%) ofcompound 225 as a colorless oil. HPLC: 99% at 2.01 min (retention time)(YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ES): m/z 376.0 [M+NH₄]⁺.

EXAMPLE 226(3aα,4β,7β,7aα)-2-(Methylsulfonyl)-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile(226)

To a solution of compound 225 (48 mg, 0.14 mmol) in CH₂Cl₂ (2 mL) wasadded mCPBA (145 mg, 50% mixture, 0.420 mmol) in one solid portion. Theresulting mixture was allowed to warm to room temperature and wasstirred for 60 h at which time no more starting material could bedetected by HPLC. The reaction was quenched by the addition of sat.NaHCO₃ solution (5 mL), the layers were separated and the aqueous layerwas extracted with CH₂Cl₂ (20 mL). The combined organic phases weredried over MgSO₄ and concentrated in vacuo. The remaining residue waspurified by reverse phase preparative HPLC (YMC S5 ODS 20×100 mm elutingwith 30-100% aqueous methanol over 10 mincontaining 0.1% TFA, 20 mL/min)to afford 48 mg (0.13 mmol, 92%) of compound 226 as a white solid. HPLC:100% at 2.07 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 392.0 [M+NH₄]⁺.

EXAMPLE 227(3aα,4β,5β,7β,7aα)-7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]hexahydro-5-hydroxy-4-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(227B)

A.(3aα,4β,7β,7aα)-4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-3a,4,7,7a-tetrahydro-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(227A)

A solution of compound 204A (455 mg, 1.89 mmol) and1-[4-nitronaphthalene]-1H-pyrrole-2,5-dione (254 mg, 0.947 mmol,prepared as described for4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1′-naphthalenecarbonitrile, Example223A) in benzene (2 mL) was heated at 60° C. overnight. The reactionmixture was concentrated under reduced pressure to give crude compound227A as a brown solid, which was used directly in the next step withoutfurther purification.

B.(3aα,4β,5β,7β,7aα)-7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]hexahydro-5-hydroxy-4-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(227B)

BH₃.THF (0.95 mL, 0.95 mmol, 1M in THF) was added to a solution of crudecompound 227A (0.48 g, 0.95 mmol) in THF (2 mL) at 0° C. After compound227A was consumed, as was evident by HPLC, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was thendissolved in toluene (2 mL), Me₃NO (71.0 mg, 2.84 mmol) was added andthe mixture was heated to reflux overnight. The reaction mixture wasthen cooled to rt, added to H₂O and extracted with EtOAc (3×). Thecombined organic layers were dried over MgSO₄ and concentrated underreduced pressure. Purification by flash chromatography on SiO₂ elutingwith 75% EtOAc/hexanes, gave 130 mg (26%) of compound 227B as a brownsolid. HPLC: 94% at 3.92 min (retention time) (YMC S5 ODS column 4.6×50mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 527.5[M+H]⁺.

EXAMPLE 228(3aα,4β,5β,7β,7aα)-Hexahydro-5-hydroxU-7-(2-hydroxyethyl)-4-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(228)

A mixture of TBAF (0.3 mL, 0.3 mmol, 1 M solution in THF) and HF (0.3mL, 50% in H₂O) in CH₃CN (6 mL) was added to a solution of 227B (104 mg,0.197 mmol) in THF (2 mL) at 0° C. The reaction mixture was stirredovernight at rt. After the starting material was consumed, as wasevident by TLC, H₂O and EtOAc were added and the layers were separated.The aqueous layer was extracted with EtOAc (1×) and the combined organiclayers were washed with H₂O (1×) and brine (1×), dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by flashchromatography on SiO₂ eluting with 5% MeOH/CH₂Cl₂ gave 61 mg (75%) ofcompound 228 as a yellow solid. HPLC: 99% at 2.47 min (retention time)(YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ES): m/z 411.2 [M−H]⁻.

EXAMPLE 229(3aα,4β,5β,7β,7aα)-7-[2-(4-Fluorophenoxy)ethyl]hexahydro-5-hydroxy-4-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(229)

DBAD (37.7 mg, 0.164 mmol) was added to a solution of PPh₃ (43.0 mg,0.164 mmol) in THF (1 mL). After stirring for 10 min, 4-fluorophenol(18.3 mg, 0.164 mmol) was added and the reaction mixture was stirred fora further 5 min. A solution of compound 228 (45.0 mg, 0.109 mmol) in THF(1 mL) was added and the mixture was stirred at rt overnight. HPLCshowed the crude reaction mixture to contain mostly starting diol(compound 228), so this mixture was added to a preformed mixture asbefore of PPh₃ (86 mg), DBAD (75.4 mg) and phenol (36.6 mg) in THF (4mL) at rt. Stirring was continued until all of compound 228 wasconsumed. The reaction was then concentrated under reduced pressure.Purification by reverse phase preparative HPLC [15.2 min (retentiontime) (YMC S5 ODS A column 20×100 mm, 10-90% aqueous methanol over 15minutes containing 0.1%. TFA, 20 mL/min, monitoring at 220 nm)] gave25.0 mg (45%) of compound 229 as a light yellow solid. HPLC: 99% at 3.53min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 mm). MS (ES): m/z 505.2 [M−H]⁻.

EXAMPLE 230(3aα,4β,5β,6β,7β,7aα)-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&(3aα,4β,5α,6α,7β,7aα)-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(230Bi & 230Bii. Respectively)

A.(3aα,4β,7β,7aα)-4-(1,3,3a,4,7,7a-Hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(230A)

2,5-Dimethyl furan (1.23 mL, 11.5 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(2.00 g, 7.69 mmol) were dissolved in benzene (10 mL) and heated at 60°C. for 18 h. The volatile organics were then removed in vacuo. Theresulting crude compound 230A was carried on without purification. HPLC:71% at 3.007 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm).

B.(3aα,4β,5β,6β,7β,7aα)-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&(3aα,4β,5α,6α,7β,7aα)-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(230Bi & 230Bii)

Compound 230A (0.100 g, 0.281 mmol) was dissolved in acetone andN-methylmorpholine-N-oxide (50% aq. solution, 0.10 mL, 0.42 mmol) wasadded. OsO₄ (4% aq. solution, 0.014 mmol) was then added. After 3 h at25° C., the reaction was complete and sodium sulfite (0.250 g) was addedwith vigorous stirring. After 15 min, brine (10 mL) was added and thesolution was extracted with EtOAc (3×15 mL). The organics were driedover anhydrous sodium sulfate and then concentrated in vacuo. The crudediol mixture was purified by preparative TLC eluting with 18% acetone inchloroform to give 0.038 g (34%) of compound 230Bi (beta face) and 0.012g (11%) of compound 230Bii (alpha face) as pale yellow solids. Compound230Bi: HPLC: 100% at 2.567 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z397.08 [M+H]⁺. Compound 230Bii: HPLC: 100% at 2.417 min (retention time)(YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ES): m/z 397.08 [M+H]⁺.

EXAMPLE 231(3aα,4β,5β,6β,7β,7aα)-4-[Octahydro-5,6-dihydroxy-4-(hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(231C)

A.(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-1,3,3a,4,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(231A)

Compound 204A (29.0 g, 120 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (20.0 g,80.6 mmol) were suspended in benzene (80 mL) and heated at 60° C. for 14h. The mixture was then concentrated in vacuo at 40° C. for 40 min. Theresulting slurry was cooled to 25° C. and then suspended in MeOH (200mL) and stirred at rt for 30 min. The solution was then cooled to 0° C.for 30 min and then filtered rinsing with cold MeOH. The resulting solidwas dried in vacuo to give 26.1 g (55%) of crude compound 231A as awhite solid. The methanol solution was concentrated in vacuo andresuspended in MeOH (50 mL) and cooled to −20° C. for 4 h. The solutionwas then filtered rinsing with cold MeOH. The resulting solid was driedin vacuo to give 3.8 g (10%) of compound 231A as a white solid. HPLC:95% at 4.227 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm)

B.(3aα,4β,5β,6β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5,6-dihydroxy-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(231B)

Compound 231A (0.400 g, 0.851 mmol) was dissolved in acetone (9.0 mL)and N-methylmorpholine-N-oxide (50% aq. solution, 0.150 mL, 1.28 mmol)was added. OsO₄ (4% aq. solution, 0.043 mmol) was then added. After 3 hat 25° C., the reaction was complete and sodium sulfite (1.0 g) wasadded with vigorous stirring. After 15 minutes, brine (30 mL) was addedand the solution extracted with EtOAc (3×50 mL). The organics were driedover anhydrous sodium sulfate and then concentrated in vacuo. The crudediol was purified by flash chromatography on silica eluting with 5-25%acetone in chloroform to give 0.355 g (80%) of compound 231B as a yellowsolid. HPLC: 93% at 3.903 min (retention time) (YMC S5 ODS column 4.6×50mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 522.00[M+H]⁺.

C.(3aα,4β,5β,6β,7β,7aα)-4-[Octahydro-5,6-dihydroxy-4-(hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(231C)

Compound 231B (0.400 g, 0.766 mmol) was dissolved in THF (5.0 mL) andtransferred to a polypropylene bottle and cooled to 0° C. HFoPyridine(1.0 mL) was then added. After 20 min, the reaction was carefully pouredinto cold sat. aq. sodium bicarbonate and extracted with methylenechloride (3×30 mL). The organics were then washed once with 1 N HCl anddried over anhydrous sodium sulfate. Concentration in vacuo gave 0.290 g(93%) compound 231C (0.290 g) as a yellow foam which was not purifiedfurther. HPLC: 92% at 2.273 and 2.423 min (atropisomers, retention time)(YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ES): m/z 409.10 [M+H]⁺.

EXAMPLE 232(3aα,4β,5β,6β,7β,7aα)-4-[Octahydro-5,6-dihydroxy-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile,(232C)

A. 2-Methyl-5-[2-[4-(trifluoromethyl)phenoxy]ethyl]furan (232A)

To a solution of triphenylphosphine (1.56 g, 5.95 mmol) in THF (40 mL)was added DBAD (1.37 g, 5.95 mmol). After 10 min,4-trifluoromethylphenol (0.964 g, 5.95 mmol) was added. After 10additional minutes, compound 21A (0.500 g, 3.97 mmol) was added. After14 h at 25° C., the reaction was concentrated in vacuo and purified byflash chromatography on silica eluting with chloroform to give 0.713 g(44%) of compound 232A as a clear oil.

B.(3aα,4β,7β,7aα)-4-[1,3,3a,4,7,7a-hexahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(232B)

Compound 232A (0.301 g, 1.15 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(0.220 g, 0.846 mmol) were suspended in benzene (1.5 mL) and heated at60° C. for 14 h. The mixture was then concentrated in vacuo at 40° C.for 40 minutes. The crude product was purified by flash chromatographyon silica eluting with 10-0% hexanes in methylene chloride to give 0.199g (44%) of compound 232B as a yellow solid. Compound 232B wascharacterized as the exo diastereomer by NOE experiments. HPLC: 94% at3.993 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm).

C.(3aα,4β,5β,6β,7β,7aα)-4-[Octahydro-5,6-dihydroxy-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile,(232C)

Compound 232B (0.075 g, 0.14 mmol) was dissolved in acetone (2.0 mL) andN-methylmorpholine-N-oxide (50% aq. solution, 0.025 mL, 0.21 mmol) wasadded. OsO₄ (4% aq. solution, 0.007 mmol) was then added. After 3 h at25° C., the reaction was complete and sodium sulfite (0.25 g) was addedwith vigorous stirring. After 15 minutes, brine (5 mL) was added and thesolution extracted with EtOAc (3×10 mL). The organics were dried overanhydrous sodium sulfate and then concentrated in vacuo. The crude diolwas purified by preparative TLC on silica gel, eluting with 10% acetonein chloroform to give 0.038 g (48%) of compound 232C as a yellow solid.HPLC: 98% at 3.747 min (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 593.08[M+Na]⁺.

EXAMPLE 233(3aα,4β,5β,5aβ,8aβ,8bα)-4-(Decahydro-5-hydroxy-4-methyl-1,3-dioxo-4,8a-epoxy-2H-furo[3,2-e]isoindol-2-yl)-1-naphthalenecarbonitrile,(233)

To a solution of triphenylphosphine (0.072 g, 0.28 mmol) in THF (3.0 mL)was added DBAD (0.063 g, 0.28 mmol). After 10 min, 4-cyanophenol (0.033g, 0.28 mmol) was added. After 10 additional minutes, compound 231C(0.075 g, 0.18 mmol) was added. After 3 h at 25° C., the reaction wasconcentrated in vacuo and purified by preparative TLC on silica gel,eluting with 15% acetone in chloroform to give 0.068 g (95%) of compound233 as a white solid. HPLC: 95% at 2.430 and 2.560 min (atropisomers,retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). MS (ES): m/z 391.09 [M+H]⁺.

EXAMPLE 234(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-aceticacid. (234B)

A.(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)-1,2,3,3a,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-aceticacid (234A)

5-Methyl-2-furanacetic acid (0.500 g, 3.57 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (0.899 g,3.57 mmol) were dissolved in benzene (3.0 mL) and heated at 60° C. for 2h and then cooled to 25° C. After 12 h, a white solid precipitated outof solution which was collected and rinsed with diethyl ether to yield1.20 g (87%) of compound 234A as a light yellow solid. NMR analysisshowed only one diastereomer. HPLC: 86% at 2.767 min (retention time)(YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 389.45 [M+H]⁺.

B(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-aceticacid, (234B)

Compound 234A (1.10 g, 2.82 mmol) was dissolved in EtOH/EtOAc (1:1, 50mL) and 10% Pd/C (0.4 g, cat.) was added. H₂ was introduced via aballoon. After 5 h at 25° C., the reaction was filtered through Celiterinsing with EtOAc and concentrated in vacuo to yield 1.00 g (91%) ofcompound 234B as a yellow solid. HPLC: 80% at 2.84 min (retention time)(YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 391.1 [M+H]⁺.

EXAMPLE 235(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-aceticacid, methyl ester, (235)

Compound 234B (0.050 g, 0.13 mmol) was dissolved in acetonitrile (2.0mL), then DCC (0.025 g, 0.13 mmol) was added followed by HOAc (0.018 g,0.13 mmol). 4-Fluorobenzyl alcohol (0.014 mL, 0.13 mmol) was then addedand the reaction was stirred for 3 h. The reaction mixture wasconcentrated in vacuo and purified by reverse phase preparative HPLC(YMC S5 ODS 20×100 mm, 10-90% aqueous methanol over 15 min containing0.1% TFA, 20 mL/min, monitoring at 220 nm). Purification yielded 0.040 g(82%) of compound 235 as a white solid, rather than the expected benzylester. None of the anticipated benzyl ester was observed by NMR orLC-MS. HPLC: 100% at 3.033 min (retention time) (YMC S5 ODS column4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 405.51[M+H]⁺.

EXAMPLE 236(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)-N-[(4-fluorophenyl)methyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-acetamide,(236)

Compound 234B (0.10 g, 0.27 mmol) was dissolved in acetonitrile (4.0mL). HOAc (0.035 g, 0.27 mmol) and DCC (0.049 g, 0.27 mmol) were thenadded followed by 4-fluorobenzylamine (0.030 mL, 0.27 mmol). After 4 hat 25° C., the reaction was concentrated in vacuo and purified byreverse phase preparative HPLC (YMC S5 ODS 20×100 mm, 10-90% aqueousmethanol over 15 minutes containing 0.1% TFA, 20 mL/min, monitoring at220 nm) to yield 0.085 g (67%) of compound 236 as a white solid. HPLC:100% at 3.277 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 498.43 [M+H)⁺.

EXAMPLE 237(3aα,4β,7β,7aα)-N-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]-4-fluorobenzamide,(237B)

A. 4-Fluoro-N-[2-(5-methyl-2-furanyl)ethyl]benzamide (237A)

4-Fluorophenylacetyl chloride (0.290 mL, 2.44 mmol) was added dropwiseto a solution of β-(5-methyl-2-furanyl)ethanamine (300 mg, 2.44 mmol,made according to the procedure of Yur'ev et al. J. Gen. Chem. USSR(Engl. Transl.) 33, 3444-8 (1963)) in THF (2.5 mL) at rt, followed bythe dropwise addition of Et₃N (0.340 mL, 2.44 mmol). Once the startingmaterial was consumed, as was evident by HPLC, the reaction was quenchedwith H₂O and extracted with CH₂Cl₂. The combined organic layers weredried over MgSO₄ and concentrated under reduced pressure. Purificationby flash chromatography on silica gel eluting with a gradient of 0-50%EtOAc/hexane gave 523 mg (95%) of compound 237A as a white solid. HPLC:99% at 2.84 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 248.15[M+H]⁺.

B.(3aα,4β,7β,7aα)-N-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]-4-fluorobenzamide,(237B)

A solution of compound 237A (221 mg, 0.896 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (222 mg,0.896 mmol) in benzene (4 mL) was heated at 60° C. overnight. Thereaction mixture was concentrated under reduced pressure and dissolvedin EtOAc (30 mL). 10% Pd/C (50 mg) was added and the mixture was stirredunder a hydrogen balloon overnight. The reaction mixture was filteredthrough a pad of Celite and concentrated under reduced pressure.Purification by flash chromatography on silica gel eluting with 25%-75%EtOAc/hexane (gradient) gave 160 mg (36%) of compound 237B as anoff-white solid. HPLC: 97% at 3.13 & 3.23 min (atropisomers, retentiontime) (Phenomenex-prime S5-C18 column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 498.11 [M+H]⁺.

EXAMPLE 238[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile&[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.(238i & 238ii)

Racemic compound 223B was separated into its enantiomers by normal phasepreparative chiral HPLC (CHIRALPAK AD 5×50 cm column; eluting with 20%MeOH/EtOH (1:1) in heptane (isocratic) at 50 mL/min, monitoring at 220nm) to give the faster eluting compound 238i (Chiral HPLC: 13.54 min;CHIRALPAK AD 4.6×250 mm column; eluting with 20% MeOH/EtOH (1:1) inheptane at 1 mL/min) and the slower eluting compound 238ii (Chiral HPLC:14.99 min; CHIRALPAK AD 4.6×250 mm column; eluting with 20% MeOH/EtOH(1:1) in heptane at 1 mL/min). The absolute conformation for compounds238i & 238ii was not established. For simplicity in nomenclature,compound 238i is designated herein as having an “R” configuration andcompound 238ii as having an “S” configuration. Enantiomerically pureproducts derived from compound 238i are designated herein as having a“R” configuration and enantiomerically pure products derived fromcompound 238ii are designated herein as having an “S” configuration.

EXAMPLE 239[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile&[3aS-(-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.(239i & 239ii)

To a solution of triphenylphosphine (0.052 g, 0.20 mmol) in THF (2.0 mL)was added DBAD (0.046 g, 0.20 mmol). After 10 min, 3-fluorophenol (0.018mL, 0.20 mmol) was added. After 10 additional minutes, compound 238i(0.050 g, 0.13 mmol) was added. After 3 h at 25° C., the reaction wasconcentrated in vacuo and purified by reverse phase preparative HPLC(YMC S5 ODS 20×100 mm, 10-90% aqueous methanol over 15 minutescontaining 0.2% TFA, 20 mL/min, monitoring at 220 nm) to give 0.031 g(33%) of compound 239i as a white solid. This process was repeated withcompound 238ii to yield compound 239ii. Compound 239i: HPLC: 100% at3.80 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 471.65 [M+H]⁺, [α]_(D) ²⁵=−47.371(c=4.412 mg/cc, CH₂Cl₂). Compound 239ii: HPLC: 100% at 3.80 min(retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). MS (ES): m/z 471.65 [M+H]⁺, [α]_(D) ²⁵=+24.3 (c=4.165 mg/cc,CH₂Cl₂).

EXAMPLE 240 (4-Fluorophenyl)carbamic acid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester, (240)

Compound 223B (0.100 g, 0.279 mmol) was dissolved in dichloroethane (3.0mL) and 4-fluorophenylisocyanate (0.048 mL, 0.42 mmol) was addedfollowed by heating to 60° C. After 2 h, the reaction was cooled to 25°C. and diluted with methylene chloride. The mixture was washed once withsat. aq. sodium bicarbonate (20 mL) and then the organics were driedover anhydrous sodium sulfate. The crude material was purified by flashchromatography on silica gel eluting with 15% acetone in chloroform togive 0.098 g (68%) of compound 240 as a yellow foam. HPLC: 98% at 3.320& 3.457 min (atropisomers, retention time) (YMC S5 ODS column 4.6×50 mm,10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm). MS (ES): m/z 514.13 [M+H]⁺.

EXAMPLE 241(3aα,4β,7β,7aα)-4-[Octahydro-4-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(241D)

A. 2-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]furan (241A)

2-(2-Hydroxyethyl)furan (1.00 g, 8.93 mmol, Example 255A) was dissolvedin DMF at 25° C. and imidazole (0.790 g, 11.6 mmol) was added. TBSCl(1.35 g, 8.93 mmol) was then added in portions over 5 minutes. After 2h, the reaction was poured into diethyl ether (300 mL) and washedsequentially with water (1×100 mL), 1 N HCl (1×100 mL), and brine (1×100mL). The combined organics were then dried over magnesium sulfate andconcentrated in vacuo. Compound 241A was isolated as a clear oil (1.77g) and was taken on without purification. HPLC: 100% at 4.233 min(retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm).

B.(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(241B)

4-(2,5-Dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (0.721 g,3.40 mmol) was suspended in benzene (5.0 mL) in a sealed tube andcompound 241A (1.00 g, 4.42 mmol) was added. The reaction was heated at60° C. for 16 h and then cooled to 25° C. The benzene was removed invacuo to give a yellow solid. The crude material was purified by flashchromatography on silica gel eluting with 1-5% acetone in chloroform togive 1.37 g (85%) of compound 241B as a yellow solid. NMR experimentsconfirmed the exo isomer assignment. HPLC: 100% at 4.030 & 4.110 min(atropsiomers, retention time) (YMC S5 ODS column 4.6×50 mm, 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

C.(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(241C)

Compound 241B (0.500 g, 1.14 mmol) was dissolved in ethyl acetate (40mL) and 10% Pd/C (0.200 g) was added. Hydrogen was then introduced via aballoon. After 4 h, the reaction was filtered through Celite, rinsedwith ethyl acetate and concentrated in vacuo to yield a pale yellowsolid, which was purified by flash chromatography on silica gel elutingwith acetone/chloroform (0%-1.5%-3% acetone) to give 0.450 g (83%) ofcompound 241C as a yellow foam.

D.(3aα,4β,7β,7aα)-4-[Octahydro-4-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(241D)

Compound 241C (0.283 g, 0.594 mmol) was dissolved in a solution of 2%conc. HCl in absolute ethanol (10 mL). After 1 h, the reaction wasquenched with sat. aq. sodium bicarbonate and extracted with methylenechloride (4×20 mL). The combined organics were dried over sodium sulfateand concentrated in vacuo to give 0.211 g (98%) of compound 241D as awhite solid. HPLC: 100% at 2.14 min (retention time) (YMC S5 ODS column4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 363.45[M+H]⁺.

EXAMPLE 242(3aα,4β,6β,7β,7aα)-4-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-6-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(242C)

A.(3aα,4β,6β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-6-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(242A)

Compound 241B (1.00 g, 2.28 mmol) and Wilkinson's catalyst (0.105 g,0.114 mmol) were stirred rapidly under vacuum at 25° C. for 1 h and thenpurged with N₂. THF (30 mL) was then added followed by catecholborane(0.487 mL, 4.57 mmol) after the olefin was completely dissolved. After 1h, the reaction was cooled to 0° C. and a pH 7.2 phosphate buffer (33mL) was added followed by EtOH (13 mL) and H₂O₂ (30% aq. soln, 3.0 g).After 3 h at 0° C. the reaction was complete by LC and the mixture wasextracted with methylene chloride (3×50 mL). The combined organics werewashed with a 1:1 mixture of 10% sodium sulfite/1 N NaOH (50 mL) andonce with brine (50 mL). All aqueous phases were combined and extractedwith methylene chloride (50 mL) and the organic phase combined with theprevious extractions. All the organics were then dried over anhydroussodium sulfate and then concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel eluting with 10-20%acetone in chloroform to give 0.634 g of compound 242A as a white foam.HPLC: 96% at 3.797 min (retention time) (YMC S5 ODS column 4.6×50 mm,10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm). MS (ES): m/z 493.13 [M+H]⁺.

B.(3aα,4β,6β,7β,7aα)-4-[Octahydro-6-hydroxy-4-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(242B)

Compound 242A (0.400 g, 0.813 mmol) was dissolved in a solution of 2% 12N HCl in absolute ethanol (10 mL). After 1 h, the reaction was quenchedwith sat. aq. sodium bicarbonate and extracted with EtOAc (4×20 mL). Thecombined organics were dried over sodium sulfate and concentrated invacuo to give 0.305 g of compound 242B as a white solid. HPLC: 90% at2.043 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 379.09 [M+H]⁺.

C.(3aα,4β,5β,7β,7aα)-4-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-6-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(242C)

To a solution of triphenylphosphine (0.054 g, 0.207 mmol) in THF (2.0mL) was added DBAD (0.048 g, 0.207 mmol). After 10 min, 4-cyanophenol(0.025 g, 0.207 mmol) was added. After 10 additional minutes, compound242B (0.050 g, 0.138 mmol) was added. After 3 h at 25° C., the reactionwas concentrated in vacuo and purified by preparative TLC on silicaeluting with 25% acetone/chloroform to give 0.056 g of compound 242C asa white solid. HPLC: 90% at 2.987 min (retention time) (YMC S5 ODScolumn 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 480.10[M+H]⁺.

EXAMPLE 243[3aS-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile&[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.(243Di & 243Dii)

A.(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(243A)

4-(2,5-Dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (18.3 g,68.7 mmol) was added to a solution of compound 204A (26.6 g, 110.6 mmol)in benzene (75 mL) and heated at 60° C. overnight. After cooling to rt,the reaction mixture was concentrated under reduced pressure. Theresidue was treated with MeOH (250 mL) with stirring at 0° C. for 10min. The resulting solid was filtered, washed with cold MeOH (2×10 mL)and dried to give 26.7 g (79.5%) of compound 243A as a yellow solid.HPLC analysis of the above solid revealed it to be 95% pure (HPLCconditions: 95% at 2.48 min (retention time) (Phenomenex-prime S5-C18column, 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with0.2% H₃PO₄, detecting at 220 nm)). The filtrate was then concentratedunder reduced pressure and the resulting solid was chromatographed,eluting with 3% acetone/CHCl₃, to give an additional 4.36 g of compound243A (13%), giving a total final yield of 92.5%.

B.(3aα,4β,5β,7β,7aα)-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(243B)

A mixture of 243A (10 g, 20.46 mmol) and RhCl(PPh₃)₃ (0.947 mg, 1.02mmol) was evacuated and filled with argon (3×). THF (200 mL) was addedand once all particulates had dissolved, catecholborane (4.4 mL, 40.93mmol) was slowly added dropwise. When the formation of product ceased,as was determined by HPLC, the reaction mixture was cooled to 0° C. andquenched with phosphate buffer (330 mL, pH 7.2) then EtOH (130 mL) andH₂O₂ (300 mL, 30% aq. sol) were added. Once boronate was consumed, themixture was extracted with CH₂Cl₂ (3×) and the combined organic layerswere washed with 1 N NaOH, 10% aq. NaHSO₃ (1:1, 1×) and brine (1×). Thecombined washes was extracted with CH₂Cl₂ (1×) and the combined organiclayers were dried over Na₂SO₄. Purification by flash chromatography onsilica gel eluting with 10% to 30% acetone/CHCl₃ gradient over 25 mingave 7.1 g (68%) of 243B as a light yellow solid. HPLC conditions: 98%at 3.82 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm,10%-90% aqueous methanol over 4 minute gradient with 0.2% H₃PO₄,detecting at 220 nm).

C.[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile&[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(243Ci & 243Cii)

The racemic compound 243B was separated into the individual enantiomersby chiral normal phase liquid chromatography. A Chiralpak OD column(50×500 mm) was used, eluting with 13% EtOH/hexanes over 99 min at 50mL/min detecting at 220 nm. The faster eluting isomer compound 243Ci hada retention time=45 min and the slower eluting isomer compound 243Ciihad a retention time=66 min.

D.[3aS-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile&[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(243Di & 243Dii)

Compound 243Ci (0.84 g, 2.14 mmol) was dissolved in 2% 12 N HCl/EtOH (20mL), stirred for 5 minutes and concentrated under reduced pressure.Purification by flash chromatography on silica gel eluting with 5-10%MeOH/CH₂Cl₂ gave 0.57 g (88%) of 243Di. Compound 243Di which came fromthe faster eluting isomer (243Ci) was found to be 99.7% ee by analyticalnormal phase chiral chromatography. HPLC conditions: 99.7% at 2.17 min(retention time) (Chiralcel OJ 44.6×250 mm, 10 micron, 40° C., isocratic80% Heptane/20% EtOH/MeOH (1:1), 1.0 mL/min., detection at 288 nm).

Compound 243Cii (0.86 g, 2.19 mmol) was dissolved in 2% 12 N HCl/EtOH(20 mL), stirred for 5 minutes and concentrated under reduced pressure.Purification by flash chromatography on silica gel eluting with 5-10%MeOH/CH₂Cl₂ gave 0.60 g (90%) of 243Dii. Compound 243Dii which came fromthe slower eluting isomer (243Cii) was found to have 87.1% ee byanalytical chiral phase chiral chromatography. HPLC conditions: 87.1% at18.4 min (retention time) (Chiralcel OJ 44.6×250 mm, 10 micron, 40° C.,isocratic 80% heptane/20% EtOH/MeOH (1:1), 1.0 mL/min., detection at 288nm).

The absolute conformation for compounds 243Di & 243Dii was notdetermined. For simplicity in nomenclature, compound 243Di is designatedherein as having an “S” configuration and compound 243Dii as having an“R” configuration. Enantiomerically pure products derived from compound243Di are designated herein as having an “S” configuration andenantiomerically pure products derived from compound 243Dii aredesignated herein as having an “R” configuration

EXAMPLE 244[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(4-Cyanophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile&[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(4-Cyanophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(244i & 244ii)

DBAD (26 mg, 0.115 mmol) was added to a solution of PPh₃ (30 mg, 0.115mmol) in THF (0.65 mL). After stirring for 10 min, 4-cyanophenol (13.6mg, 0.115 mmol) was added and the reaction mixture was stirred for afurther 5 min. Compound 243Di (30 mg, 0.076 mmol) was added and themixture was stirred at rt for 1 h. The reaction was concentrated underreduced pressure. Purification by flash chromatography on silica geleluting with 30% acetone/70% CHCl₃ gave 23.1 mg (0.047 mmol, 61.7%) ofcompound 244i. HPLC conditions: 95% at 3.06 min (retention time) (YMC S5ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2%H₃PO₄, detecting at 220 nm). MS (ES): m/z 494.09 [M+H]⁺. [α]_(D)=53.30°,C=4.5 mg/cc in THF, @589 nm)

DBAD (26 mg, 0.115 mmol) was added to a solution of PPh₃ (30 mg, 0.115mmol) in THF (0.65 mL). After stirring for 10 min, 4-cyanophenol (13.6mg, 0.115 mmol) was added and the reaction mixture was stirred for afurther 5 min. Compound 243Dii (30 mg, 0.076 mmol) was added and themixture was stirred at rt for 1 h. The reaction was concentrated underreduced pressure. Purification by flash chromatography on silica geleluting with 30% acetone/70% CHCl₃ gave 20.3 mg (0.041 mmol, 54.2%) ofcompound 244ii. HPLC conditions: 90% at 3.07 min (retention time) (YMCS5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with0.2% H₃PO₄, detecting at 220 nm). MS (ES): m/z 494.09 [M+H]⁺.[α]_(D)=−42.87°, C=6.6 mg/cc in THF, @589 nm)

EXAMPLE 245(3aα,4β,7β,7aα)-4-[4-[2-(4-Cyanophenoxy)ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(245D)

A. 2-Ethyl-5-(2-hydroxyethyl)furan (245A)

n-BuLi (2.5 M in hexane, 4.4 mL, 11 mmol) was added to a solution of2-ethylfuran (1.05 mL, 10 mmol) in THF (10 mL) at −25° C. The solutionwas warmed to rt and stirred for 3 h. Ethylene oxide (0.75 mL) was addedat −78° C. The reaction was stirred for 0.5 h at −15° C. and overnightat rt. Aqueous sat. NH₄Cl was added and the mixture was extracted withether (3×). The combined extracts were washed with water (1×) and brine(1×) and dried over Na₂SO₄. Purification by flash chromatography onsilica gel eluting with 30% EtOAc/70% hexane gave 1.12 g (8.02 mmol,80.2%) of compound 245A as a yellow oil.

B.(3aα,4β,7β,7aα)-4-[4-Ethyl-1,3,3a,4,7,7a-hexahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(245B)

A solution of compound 245A (280 mg, 2.00 mmol) and the4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (496 mg,2.00 mmol) in benzene (2 mL) was stirred at 60° C. for 2 h. The reactionmixture was concentrated under reduced pressure. The yellow solid,compound 245B, was used directly in the next step.

C.(3aα,4β,7β,7aα)-4-[4-Ethyloctahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(245C)

A mixture of compound 245B (764 mg, 1.97 mmol) and 10% Pd/C (115 mg,cat.) in EtOAc (36 mL) was stirred under a hydrogen atmosphere at rt for2 h. The reaction mixture was filtered through Celite and concentratedunder reduced pressure to give 779 mg of crude compound 245C.Purification of this crude product by flash chromatography on silica geleluting with 70% EtOAc/30% hexane gave 235 mg (0.6 mmol, 30.1%) ofcompound 245C. HPLC conditions: 99% at 2.84 min (retention time) (YMC S5ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2%H₃PO₄, detecting at 220 nm). MS (ES): m/z 391.12 [M+H]⁺.

D.(3aα,4β,7β,7aα)-4-[4-[2-(4-Cyanophenoxy)ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(245D)

DBAD (44.2 mg, 0.192 mmol) was added to a solution of PPh₃ (50.4 mg,0.192 mmol) in THF (1 mL). After stirring for 10 min, 4-cyanophenol (23mg, 0.192 mmol) was added and the reaction mixture was stirred for anadditional 5 min. Compound 245C (50 mg, 0.128 mmol) was added and themixture was stirred at rt for 2 h. The reaction was concentrated underreduced pressure. Purification by flash chromatography on silica geleluting with 40% EtOAc/60% hexane gave 43 mg (0.087 mmol, 68.4%) ofcompound 245D as a white solid. HPLC conditions: 99% at 3.65 min(retention time) (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4minute gradient with 0.2% H₃PO₄, detecting at 220 nm). MS (ES): m/z492.16 [M+H]⁺.

EXAMPLE 246(3aα,4β,7β,7aα)-4-[2-(Acetyloxy)ethyl]-2-(4-cyano-1-naphthalenyl)hexahydro-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione,(246)

Compound 223B (0.100 g, 0.279 mmol) was dissolved in methylene chloride(3.0 mL) at 25° C. and pyridine (0.071 mL, 0.837 mmol) and 4-DMAP (1.0mg) were added. Acetic anhydride (0.053 mL, 0.559 mmol) was then addedand the reaction was stirred for 20 h at 25° C. After 20 h, sat. aq.sodium bicarbonate was added and the reaction was stirred for 30 min.The mixture was then extracted with methylene chloride (2×20 mL). Theorganics were then washed once with 1 N HCl (10 mL) and then dried overanhydrous sodium sulfate. After concentration in vacuo, the crudematerial was purified by preparative TLC on silica eluting with 12%acetone in chloroform to give 0.073 g of compound 246 as a yellow foam.HPLC: 95% at 2.837 and 3.027 min (atropisomers, retention time) (YMC S5ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z441.10 [M+Na]⁺.

EXAMPLE 247(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(2-oxoethyl)-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(247)

Oxalyl chloride (2.0 M soln, 1.73 mL, 3.5 mmol) was added to drymethylene chloride (10 mL) and cooled to −78° C. DMSO (0.283 mL, 3.99mmol) was then added dropwise with the evolution of gas. After 15 min,compound 223B (1.00 g, 2.66 mmol) was then added in methylene chloride(10 mL). After 15 min, TEA (1.10 mL, 7.98 mmol) was added and thereaction was slowly warmed to 25° C. Water (30 mL) was then added andthe mixture was diluted with methylene chloride (100 mL). The organicswere then washed once with 1 N HCl (30 mL), once with water (30 mL) andonce with brine (30 mL) and then dried over anhydrous sodium sulfate.The crude product was isolated by concentration in vacuo to yieldcompound 247 as an orange foam. Crude compound 247 was taken on directlyto the next reaction. HPLC: 100% at 2.70 min (retention time) (YMC S5ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z483.65 [M+H]⁺.

EXAMPLE 248[3aα,4β(E),7β,7aα]-4-[4-[3-(4-Cyanophenyl)-2-propenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile&[3aα,4β(Z),7β,7aα]-4-[4-[3-(4-Cyanophenyl)-2-propenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(248i & 248ii)

(4-cyanobenzyl)-triphenylphosphonium chloride (0.072 g, 0.174 mmol) wassuspended in THF (2.0 mL) and cooled to 0° C. n-BuLi (1.6 M soln, 0.092mL, 0.147 mmol) was then added dropwise resulting in a homogenoussolution. The solution warmed to 25° C. for 15 min and then cooled to 0°C. Compound 247 (0.050 g, 0.134 mmol) was then added in THF. After 1 h,the reaction was quenched with sat. aq. ammonium chloride and thenextracted with methylene chloride (3×20 mL). The combined organics weredried over anhydrous sodium sulfate and then concentrated in vacuo. Thecrude material was purified by preparative TLC eluting with 5% acetonein chloroform to give 0.010 g of a mixture of compounds 248i & 248ii asa white solid. A 1:1 mixture of E and Z olefin isomers characterized byNMR spectroscopy. HPLC: 100% at 3.517 min (retention time) (YMC S5 ODScolumn 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 474.2[M+H]⁺.

EXAMPLE 249(3aα,4β,7β,7aα)-4-[4-[3-(4-Cyanophenyl)propyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(249)

The mixture of compounds 248i & 248ii (0.008 g, 0.017 mmol) wasdissolved in EtOH (3.0 mL) and Pd/C (10% Pd, 0.008 g) was added. H₂ wasthen introduced via a balloon. After 18 h, the reaction was filteredthrough Celite, eluting with EtOAc, followed by concentration in vacuo.Compound 249 was isolated as a white solid (0.007 g). HPLC: 90% at 3.520min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 476.13 [M+H]⁺.

EXAMPLE 250(3aα,4β,7β,7aα)-4-[4-[2-[(6-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(250)

To a solution of PPh₃ (52 mg, 0.20 mmol) in 0.5 mL THF was added DBAD(46 mg, 0.20 mmol) as one solid portion. The resulting mixture wasstirred for 10 min before 6-chloro-3-hydroxy-1,2-benzisoxazole (34 mg,0.20 mmol) was added. Stirring was continued for 10 min before asolution of compound 223B (50 mg, 0.13 mmol) in 0.5 mL THF wasintroduced via canula. The resulting mixture was stirred at ambienttemperature for 24 h, concentrated in vacuo and purified by reversephase preparative HPLC (YMC S5 ODS 20×100 mm column; eluting with30-100% aqueous MeOH containing 0.1% TFA over 10 min at 20 mL/min) toyield a white solid. The obtained solids were dissolved in CH₂Cl₂,washed with sat. NaHCO₃ solution, dried over Na₂SO₄ and concentrated invacuo to yield 50 mg (71%) of compound 250 as a colorless oil. HPLC:3.89 min & 4.02 min (atropisomers, retention time) (YMC S5 ODS column4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 minutes containing0.2% H3PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 528.4 [M+H]⁺.

EXAMPLE 251(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-7-[2-[(6-nitro-1H-indazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(251)

To a solution of compound 223B (50 mg, 0.13 mmol) in toluene (1 mL) wasadded ADDP (50 mg, 0.20 mmol), 6-nitro-3-indazolinone (36 mg, 0.20 mmol)and n-Bu₃P (50 μL, 0.2 mmol). The resulting mixture was heated at 80° C.for 24 h, concentrated in vacuo and purified by a combination of reversephase preparative HPLC (YMC S5 ODS 20×100 mm column; eluting with30-100% aqueous MeOH containing 0.1% TFA over 10 min at 20 mL/min) andflash chromatography (silica gel, 25% acetone in CHCl₃) to give 17 mg(25%) of compound 251 as a yellow solid. HPLC: 3.60 min & 3.74 min(atropisomers, retention time) (YMC S5 ODS column 4.6×50 mm Ballistic,10-90% aqueous methanol over 4 minutes containing 0.2% H₃PO₄, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 537.6 [M+H]⁺.

EXAMPLE 252[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(252)

PPh₃ (47 mg, 0.18 mmol), DBAD (41 mg, 0.18 mmol),3-hydroxy-1,2-benzisoxazole (24 mg, 0.18 mmol) and compound 243Di (35mg, 0.09 mmol) were reacted according to the procedure given forcompound 250. Purification was achieved by reverse phase HPLC (YMC S5ODS 20×100 mm column; eluting with 30-100% aqueous MeOH containing 0.1%TFA over 10 min at 20 mL/min) to yield a white solid. The obtainedsolids were dissolved in CH₂Cl₂, washed with sat. NaHCO₃ solution, driedover Na₂SO₄ and concentrated under reduced pressure to furnish 29 mg(64%) of compound 252 as a colorless oil. HPLC: 96% at 3.29 min(atropisomers, retention time) (YMC S5 ODS column 4.6×50 mm Ballistic,0-100% aqueous methanol over 4 minutes containing 0.2% H₃PO₄, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 510.2 [M+H]⁺.

EXAMPLE 253[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(253)

PPh₃ (47 mg, 0.18 mmol), DBAD (41 mg, 0.18 mmol),3-hydroxy-1,2-benzisoxazole (24 mg, 0.18 mmol) and compound 243Dii (35mg, 0.09 mmol) were reacted according to the procedure given forcompound 250. Purification was achieved by reverse phase HPLC (YMC S5ODS 20×100 mm column; eluting with 30-100% aqueous MeOH containing 0.1%TFA over 10 min at 20 mL/min) to yield a white solid. The obtainedsolids were dissolved in CH₂Cl₂, washed with sat. NaHCO₃ solution, driedover Na₂SO₄ and concentrated under reduced pressure to furnish 23 mg(51%) of compound 253 as a colorless oil. HPLC: 95% at 3.29 min(atropisomers, retention time) (YMC S5 ODS column 4.6×50 mm Ballistic,0-100% aqueous methanol over 4 minutes containing 0.2% H₃PO₄, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 510.4 [M+H]⁺.

EXAMPLE 254[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile,(254i & 254ii)

Racemic compound 221B was separated into its enantiomers by normal phasepreparative chiral HPLC (CHIRALPAK AD 5×50 cm column; eluting with 20%MeOH/EtOH (1:1) in heptane (isocratic) at 50 mL/min) to give the fastereluting compound 254i (Chiral HPLC: 10.02 min; CHIRALPAK AD 4.6×250 mmcolumn; eluting with 20% MeOH/EtOH (1:1) in heptane at 1 mL/min) and theslower eluting 254ii (Chiral HPLC: 14.74 min; CHIRALPAK AD 4.6×250 mmcolumn; eluting with 20% MeOH/EtOH (1:1) in heptane at 1 mL/min). (Namesof title compounds based on absolute stereochemistry determination).

EXAMPLE 255(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile&(3aα,4α,7α,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile,(255Hi & 255Hii)

A. 2-(2-Hydroxyethyl)furan (255A)

2-(2-Hydroxyethyl)furan was made in accordance with the followingreference: Harmata, M, et al. J. Org. Chem. 60, 5077-5092 (1995). n-BuLi(2.5 M in hexane, 44 mL, 110 mmol) was added to a solution of furan (8mL, 110 mmol) in 100 mL of THF at −78° C. The solution was stirred at 0°C. for 4 h and then ethylene oxide (7.5 mL) was added at −78° C. Thereaction mixture was stirred at −15° C. for 1 h and then overnight atrt. The reaction was quenched with sat. NH₄Cl and extracted with ether(3×). The combined extracts were washed with water (1×) and brine (1×).The ether solution was dried over Na₂SO₄ and concentrated under reducedpressure. Purification by flash chromatography on silica gel elutingwith 40% EtOAc/60% hexane gave 5.4 g (48.2 mmol, 43.8%) of compound 255Aas a light brown oil.

B. 2-[2-[[(1,1-Dimethlethyl)dimethylsilyl]oxy]ethyl]furan (255B)

Imidazole (3.65 g, 53.6 mmol) and TBSCl (6.47 g, 42.9 mmol) were addedto the solution of compound 255A (4.00 g, 35.7 mmol) in 50 mL of DMF.The mixture was stirred at rt for 2 h and then the reaction mixture waspoured into ether. The ether solution was washed with water (1×), 1 NHCl (1×), water (1×) and brine (1×). The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with 30% CH₂Cl₂/70% hexane gave 7.4g (32.7 mmol, 91.7%) of 255B as a colorless oil.

C.2-[2-[[(1,1-Dimethlethyl)dimethylsilyl]oxy]ethyl]-5-(2-hydroxyethyl)furan(255C)

t-BuLi (1.2 M in pentane, 10 mL, 16.99 mmol) was added to a stirredsolution of 255B (3.49 g, 15.44 mmol) in 13 mL of THF at −78° C.dropwise. The mixture was stirred for an additional 4 h at 0° C.Ethylene oxide (1.05 mL) was added at −78° C. to the reaction solution.The mixture was warmed to rt and stirred overnight. Aqueous sat. NH₄Clwas added and most of the THF was removed under reduced pressure. Themixture was extracted with ether (3×) and the combined organic layerswere washed with water (1×) and brine (1×) and dried over Na₂SO₄.Purification by flash chromatography on silica gel eluting with 5%EtOAc/95% CH₂Cl₂ gave 2.8 g (10.4 mmol, 67%) of compound 255C as ayellow oil.

D.2-[2-[[(1,1-Dimethlethyl)dimethylsilyl]oxy]ethyl]-5-[2-(phenylmethoxy)ethyl]furan(255D)

The alcohol 255C (1.00 g, 3.7 mmol) in 12 mL of THF was treated with 60%NaH (177.8 mg, 4.44 mmol), benzyl bromide (0.53 mL, 4.44 mmol) andtetrabutylammonium iodide (50 mg, 5%) for 3 h at rt. Water was added andthe mixture was extracted with EtOAc (3×). The combined extracts werewashed with water (1×) and brine (1×) and dried over Na₂SO₄.Purification by flash chromatography on silica gel eluting with 20%hexane/80% CH₂Cl₂ gave 1.10 g (3.05 mmol, 82.6%) of compound 255D as ayellow oil.

E. 2-(2-Hydroxyethyl)-5-[2-(phenylmethoxy)ethyl]furan (255E)

Tetrabutylammonium fluoride (1.0M in THF, 3.06 mL, 3.06 mmol) was addedto the solution of compound 255D (1.1 g, 3.06 mmol) in 10 mL of THF at0° C. The reaction mixture was stirred at rt for 10 minutes, quenched bysat. NH₄Cl and extracted with ether (3×). The combined extracts weredried over Na₂SO₄. Purification by flash chromatography on silica geleluting with 10% EtOAc/90% CH₂Cl₂ gave 750 mg (3.05 mmol, 99.6%) ofcompound 255E as a light yellow oil.

F. 5-[2-(Phenylmethoxy)ethyl]furan-2-propanenitrile (255F)

DEAD (1.285 mL, 8.17 mmol) was added to a stirred solution of Ph₃P (2.14g, 8.17 mmol) in 12 mL of dry THF at 0° C. The solution was stirred for30 min at rt and compound 255E (670 mg, 2.72 mmol) was added. Thereaction was stirred for 15 min and acetone cyanohydrin (0.745 mL, 8.17mmol) was added at −15° C. The reaction was stirred for 30 min at −15°C., then at rt overnight. The mixture was then concentrated underreduced pressure. Purification by flash chromatography on silica geleluting with 100% CH₂Cl₂ gave 180 mg (0.705 mmol, 26%) of compound 255Fas a colorless oil.

G.(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)-1,2,3,3a,7,7a-hexahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile(255G)

A solution of compound 255F (180 mg, 0.706 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (263 mg,1.06 mmol) in CH₂Cl₂ (3 mL) was stirred at rt for 3 days. The reactionmixture was concentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with 5% EtOAc/CH₂Cl₂ gave 318 mg(0.63 mmol, 89.6%) of compound 255G as a light gray solid which was useddirectly in the next step.

H.(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile&(3aα,4α,7α,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile(255Hi & 255Hii)

A mixture of compound 255G (318 mg, 0.63 mmol) and 10% Pd/C (64 mg) inEtOH (10 mL) and EtOAc (5 mL) was stirred under a hydrogen atmosphere atrt overnight. The reaction mixture was filtered through Celite andconcentrated under reduced pressure to give 320 mg of crude compounds255Hi & 255Hii. Purification of 25 mg of this crude product by flashchromatography on silica gel eluting with 55% EtOAc/hexane gave 6.5 mg(0.013 mmol, 26% (based on 25 mg)) of compound 255Hi & 8.1 mg (0.016mmol, 32.4% (based on 25 mg)) of compound 255Hii. Compound 255Hi: HPLCconditions: 98% at 3.57 min (retention time) (YMC S5 ODS 4.6×50 mm,10%-90% aqueous methanol over 4 minute gradient with 0.2% H₃PO₄,detecting at 220 nm, MS (ES): m/z 506.15 [M+H]⁺. Compound 255Hii: HPLCconditions: 98% at 3.51 min (retention time) (YMC S5 ODS 4.6×50 mm,10%-90% aqueous methanol over 4 minute gradient with 0.2% H₃PO₄,detecting at 220 nm). MS (ES): m/z 506.15 [M+H]⁺.

EXAMPLE 256(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-4H-isoindole-4-propanenitrile&(3aα,4α,7α,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-4H-isoindole-4-propanenitrile,(256i & 256ii)

A mixture of compounds 255Hi & 255Hii (200 mg, 0.396 mmol) and PdCl₂(8.4 mg, cat.) in EtOH (1 mL) and EtOAc (3 mL) was stirred under ahydrogen atmosphere (30 psi) at rt overnight. The reaction mixture wasfiltered through Celite and concentrated under reduced pressure.Purification by flash chromatography on silica gel eluting with 5%MeOH/CH₂Cl₂ followed by a second column eluting with 100% EtOAc gave28.9 mg (0.0696 mmol, 17.6%) of compound 256ii and 26.5 mg (0.0639 mmol,16.1%) of compound 256i. Compound 256ii: HPLC conditions: 90% at 2.44min (retention time) (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanolover 4 minute gradient with 0.2% H₃PO₄, detecting at 220 nm.). MS (ES):m/z 416.11 [M+H]⁺. Compound 256i: HPLC conditions: 99% at 2.47 min(retention time) (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4minute gradient with 0.2% H₃PO₄, detecting at 220 nm). MS (ES): m/z416.11 [M+H]⁺.

EXAMPLE 257(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)-7-[2-(4-fluorophenoxy)ethyl]octahydro-1,3-dioxo-4,7-epoxy-4H-isoindole-4-propanenitrile,(257)

DBAD (15 mg, 0.065 mmol) was added to a solution of PPh₃ (17 mg, 0.065mmol) in THF (0.3 mL). After stirring for 10 min, 4-fluorophenol (7.33mg, 0.065 mmol) was added and the reaction mixture was stirred for afurther 5 min. Compound 256i (18.1 mg, 0.044 mmol) was added and themixture was stirred at rt for 3 h. The reaction was concentrated underreduced pressure. Purification by flash chromatography on silica geleluting with 60% EtOAc/30% hexane gave 5.9 mg (0.0116 mmol, 26.34%) ofcompound 257. HPLC conditions: 98% at 3.59 min (retention time) (YMC S5ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2%H₃PO₄, detecting at 220 nm). MS (ES): m/z 510.14 [M+H]⁺.

EXAMPLE 258(3aα,4β,7β,7aα)-2-(7-Chloro-2,1,3-benzoxadiazol-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione,(258)

A. 4-Amino-7-chloro-2,1,3-benzoxadiazole (258A)

A solution of 1.0 g (5.02 mmol) of 4-chloro-7-nitrobenzofurazan in 20 mLAcOH, 10 mL EtOAc and 2 mL H₂O was heated at 50° C. and treated withiron powder (1.4 g, 251 mmol). The mixture was heated at 80° C. for 30min and then allowed to cool to rt. The mixture was filtered throughCelite eluting with EtOAc. The filtrate was washed with sat. aq. NaHCO₃,dried over MgSO₄, and concentrated under reduced pressure to givecompound 258A (0.80 g, 94%) as a red solid.

B.(3aα,4β,7β,7aα)-2-(7-Chloro-2,1,3-benzoxadiazol-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione,(258B)

Compound 258A (42 mg, 0.25 mmol) was reacted in a sealed tube withcompound 20A (73.5 mg, 0.375 mmol), MgSO₄ (75 mg, 0.625 mmol) and Et₃N(170 μL, 1.25 mmol) in 250 μL toluene according to the above proceduredescribed in example 208C to give after purification by reverse phasepreparative HPLC (YMC S5 ODS 20×100 mm eluting with 30-100% aqueousmethanol containing 0.1% TFA over 12 min, 20 mL/min) 23 mg (26%) ofcompound 258B as a yellow solid. HPLC: 97.6% at 2.87 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over 4 minutes, 4 mL/min, monitoring at220 nm). MS (DCI): m/z 347.9 [M]⁺.

EXAMPLE 259(3aα,4β,7β,7aα)-2-(7-Chloro-2-methyl-4-benzofuranyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione,(259)

7-Chloro-2-methyl-4-benzofuranamine (38 mg, 0.25 mmol, prepared inaccordance with the procedure described by Enomoto and Takemura in EP0476697 A1) was reacted in a sealed tube with compound 20A (73.5 mg,0.375 mmol), MgSO₄ (75 mg, 0.625 mmol) and Et₃N (170 μL, 1.25 mmol) in250 μL toluene according to the procedure described in example 208C togive, after purification by reverse phase preparative HPLC (YMC S5 ODS20×100 mm eluting with 30-100 aqueous methanol containing 0.1% TFA over12 min, 20 mL/min), 42 mg (47%) of compound 259 as a white solid. HPLC:98% at 3.45 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm). MS (DCI): m/z 359.9 [M]⁺.

EXAMPLE 260(3aα,4β,7β,7aα)-2-(7-Chloro-2-methylbenzo[b]thiophen-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione,(260)

A. 1-Chloro-2-(2-chloro-allylsulfanyl)-4-nitro-benzene (260A)

A solution of 2-chloro-5-nitro-benzenethiol (1.0 g, 5.27 mmol, preparedin accordance with the procedure described by Still et al. Synth. Comm.13, 1181 (1983)) in 15 mL DMF was treated with 2,3-dichloropropene (693μL, 7.52 mmol) and K₂CO₃ (433 mg, 3.13 mmol). The mixture was heated at80° C. for 2 h and then allowed to cool to rt. EtOAc (200 mL) and H₂O(100 mL) were added. The organic phase was washed with H₂O (2×250 mL),saturated aqueous NaCl (100 mL), dried over MgSO₄, and concentrated invacuo. The crude material was purified by flash column chromatography onsilica gel eluting with 20% EtOAc in hexanes to give compound 260A (1.09g, 89%) as an orange oil.

B. 4-Amino-7-chloro-2-methylbenzo[b]thiophene (260B)

A solution of 1.09 g (4.67 mmol) of compound 260A in 20 mL AcOH with 10mL EtOAc and 2 mL H₂O was heated to 80° C. and treated with iron powder(1.3 g, 23.4 mmol). The mixture was heated at 80° C. for 40 min and thenallowed to cool to rt. The mixture was filtered through Celite elutingwith EtOAc. The filtrate was washed with sat. aq. NaHCO₃, dried overMgSO₄, and concentrated in vacuo. N,N-diethylaniline (10 mL) was added,and the reaction was heated at 215° C. for 6 h. After cooling to rt, 1 Naqueous HCl (20 mL) was added, and the reaction was stirred at roomtemperature for 2 h. The mixture was extracted with EtOAc (3×30 mL). Theorganic phase was washed with saturated aqueous NaHCO₃, dried overMgSO₄, and concentrated in vacuo. The crude material was purified byflash column chromatography on silica gel eluting with 25% EtOAc inhexanes to give compound 260B (320 mg, 35%) as a beige solid.

C.(3aα,4β,7β,7aα)-2-(7-Chloro-2-methylbenzo[b]thiophen-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione,(260C)

Compound 260B (49 mg, 0.25 mmol) was reacted in a sealed tube withcompound 20A (73.5 mg, 0.38 mmol), MgSO₄ (75 mg, 0.63 mmol) and Et₃N(170 μL, 1.25 mmol) in 250 μL toluene according to the proceduredescribed in example 208C to give, after purification by reverse phasepreparative HPLC (YMC S5 ODS 20×100 mm eluting with 30-100% aqueousmethanol over 12 mincontaining 0.1% TFA, 20 mL/min), 28 mg (30%) ofcompound 260C as a pale yellow solid. HPLC: 96% at 3.18 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). MS (DCI): m/z 376.0 [M]⁺.

EXAMPLE 261[3aα,4β(E),7β,7aα]-4-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]-2-butenoicacid, phenylmethyl ester, (261)

Compound 247 (0.500 g, 1.34 mmol) was dissolved in THF (20 mL) andbenzyl(triphenylphosphoranylidene) (0.55 g, 1.34 mmol) was added. Thereaction mixture was stirred at 67° C. for 2 h and then concentratedunder reduced pressure. Purification by flash chromatography on SiO₂eluting with 5% acetone/95% CHCl₃ gave 0.65 g of compound 261 as ayellow solid. HPLC: 99% at 3.717 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z507.1 [M+H]⁺.

EXAMPLE 262(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-butanoicacid, (262)

Compound 261 (0.60 g, 1.19 mmol) was dissolved in EtOH/EtOAc (5 mL/5 mL)and 10% Pd/C (0.30 g) was added. Hydrogen was then introduced via aballoon. After 8 h the reaction was filtered through Celite and thenconcentrated under reduced pressure to give compound 262 (0.47 g) as awhite solid. HPLC: 98% at 2.81 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z419.1 [M+H]⁺.

EXAMPLE 263(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)-N-(4-fluorophenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-butanamide(263)

Compound 262 (0.030 g, 0.072 mmol) was dissolved in CH₃CN (1 mL). DCC(0.014 g, 0.072 mmol) and HOAc (0.0098 g, 0.072 mmol) were then added,followed by 4-fluoroaniline (0.007 mL, 0.072 mmol). The reaction mixturewas stirred under argon for 14 h and the crude material was dissolved inMeOH, purified by reverse phase preparative HPLC (YMC VP-ODS column,20×100 mm, eluting with 20% B to 100% B in 15 minutes and hold @ 100% Bfor 10 minutes). Compound 263 (0.020 g) was isolated as white solid.HPLC: 100% at 3.217 min (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 512.1[M+H]⁺.

EXAMPLE 264[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(Acetyloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile&[3aR-(3α,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(264 & 243Dii)

A racemic mixture of compounds 243Di & 243Dii (1.90 gram) were dissolvedin 100 mL of anhydrous THF in a 2 L flask. Anhydrous tert-butyl-methylether (900 mL) and vinyl acetate (40 mL) were transferred into the flaskwith stirring and lipase (20 g, typeII, crude, from porcine pancreas;Sigma, Cat# L3126) was added. The reaction mixture was stirred for 21 hrat rt at which point an additional 5 grams of the lipase and 20 mL ofvinyl acetate were added. The reaction was stirred at rt for anadditional 19 h, stored at 4° C. without stirring for 36 h and thenstirred at rt for another 22 h (until the desired % ee was apparent bychiral HPLC). To monitor the reaction, 200 uL of the mixture waswithdrawn and centrifuged. The supernatant (100 uL) was dried undernitrogen and the resulting residue was dissolved in 100 uL of EtOH andsubjected to HPLC analysis:

-   1) Reverse phase HPLC: Column, YMC-ODS AQ 150×4.6; flow rate, 1.2    mL/min; sample size, 10 uL

solvent A,: 1 mM HCl in water; solvent B, MeCN; monitored at 300 nm

Gradient: Time(min) 0 8 8.5 9.5 10 12 B % 30 60 85 85 30 30

-   2) Chiral-HPLC: Column, CHIRALCEL OJ 4.6×250 mm mobile phase,    hexanes/MeOH/EtOH (8:1:1) flow rate, 1 mL/min; sample size, 20 uL    monitored at both 220 and 300 nm performed at 25° C. & 40° C. (for    ee % determination of reaction mixture)

The enzyme was removed by filtration and filtrate was concentrated underreduced pressure. The resulting mixture was dissolved in CHCl₃ andadsorbed onto silica gel (63-200 microns). These solids were applied toa VLC funnel (3 cm I.D., VLC is vacuum liquid chromatography using glassfunnels having 24/40 joints at the bottom) containing a 5 cm bed heightof silica gel (25-40 microns) and a step gradient was carried out. Thegradient was 100% CHCl₃ in the first 3 fractions, followed by CHCl₃-1%MeOH (3 fractions), CHCl₃-2% MeOH (3 fractions), CHCl₃-3% MeOH (3fractions), CHCl₃-4% MeOH (3 fractions), and finally with CHCl₃-5% MeOH(3 fractions). The volume of the fractions was 100 mL until reachingCHCl₃-3% MeOH and from that point on it was 200 mL. Compound 264 elutesin the last two fractions of 100% CHCl₃ and until the first fraction ofCHCl₃-2% MeOH. Compound 243Dii elutes starting with the second fractionof CHCl₃-2% MeOH, and continues to the first fraction of CHCl₃-5% MeOH.The crude compound 243Dii contained a small amount of a colored impuritywhich was removed by a Sephadex column [LH-20 swollen in CHCl₃-MeOH(2:1), column (2.5 cm I.D. & 90 cm long) to yield 632 mg of compound243Dii. Compound 264: HPLC conditions: 98% at 7.2 min (retention time)(method 1), chiral HPLC conditions: 29.0 min @ 25° C. (method 2).Compound 243Dii: HPLC conditions: 98% at 4.6 min (retention time)(method 1), chiral HPLC conditions: 96% ee at 25.7 min (retention time)(@ 25° C.) & 19.8 min (retention time) (@ 40° C.) (method 2).

EXAMPLE 265(3aα,4β,7β,7aα(E)]-4-[Octahydro-4-methyl-1,3-dioxo-7-(4-oxo-4-phenyl-2-butenyl)-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(265)

The compound 247 (0.050 g, 0.134 mmol) was dissolved in THF (1.5 mL) and(phenacylidene)triphenylphosphorane (0.051 g, 0.134 mmol) was added. Thereaction mixture was stirred at 67° C. for 24 h and then cooled to 23°C. and concentrated in vacuo. The crude material was then purified byreverse phase preparative HPLC. (YMC VP-ODS column, 20×100 mm, elutingwith 20% B to 100% B in 15 minutes and hold @ 100% B for 10 minutes.) togive compound 265 (0.040 g) as white solid. HPLC: 100% at 3.503 min(retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 477.1 [M+H]⁺.

EXAMPLE 266(3aα,4β,7β,7aα(E)]-4-[Octahydro-4-methyl-1,3-dioxo-7-(4-hydroxy-4-phenyl-2-butyl)-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(266)

Compound 265 (0.010 g, 0.021 mmol) was dissolved in EtOH (2.0 mL) andPd/C (10% Pd, 0.005 g) was added. Hydrogen was then introduced via aballoon and the reaction was stirred at 25° C. for 3 h. The reaction wasthen filtered through Celite rinsing with EtOAc and concentrated invacuo to give compound 266 as a tan solid (0.009 g). No purification wasnecessary. HPLC: 100% at 3.38 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z503.2 [M+Na]⁺. (Where this reaction was run for 1 hour, the resultingproduct was compound 455.)

EXAMPLES 267 TO 378

Additional compounds of the present invention were prepared byprocedures analogous to those described above. The compounds of Examples267 to 378 have the following structure (L is a bond):

where G, R⁷, the compound name, retention time, molecular mass, and theprocedure employed, are set forth in Table 5. The absolute configurationfor the following compounds was not determined. For simplicity innomenclature, compound 238i is designated herein as having an “R”configuration and compound 238ii as having an “S” configuration.Enantiomerically pure products derived from compound 238i are designatedherein as having an “R” configuration and enantiomerically pure productsderived from compound 238ii are designated herein as having an “S”configuration.

The chromatography techniques used to determine the compound retentiontimes of Table 5 are as follows: LCMS═YMC S5 ODS column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4mL/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm. The molecular mass of the compounds listed inTable 5 were determined by MS (ES) by the formula m/z.

TABLE 5 Retention Compound Time Min./ Procedure Ex. No G R⁷ NameMolecular Mass of Ex. 267

(3aα,4β,7β,7aα)-(4-[7-[2-(4-Bromophenoxy)ethyl]octahydro-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile..3.97LCMS549.0[M + H]⁺ 204, 35 268

(3aα,4β,7β,7aα)-4-[Octahydro-7-[2-(4-iodophenoxy)ethyl]-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.4.09LCMS597.0[M + H]⁺ 204, 35 269

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.95LC 204, 35 270

(3aα,4β,7β,7aα)-4-[Octahydro-7-[2-(4-methoxyphenoxy)ethyl]-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.66LC 204, 35 271

(3aα,4β,7β,7aα)-4-[7-[2-(4-Ethoxyphenoxy)ethyl]octahydro-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.81LC 204, 35 272

(3aα,4β,7β,7aα)-4-[7-[2-(4-Chlorophenoxy)ethyl]octahydro-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.97LCMS522.2[M + H]⁺ 204, 35 273

(3aα,4β,7β,7aα)-4-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]benzoicacid,methyl ester. 3.77LCMS529.12[M + H]⁺ 204, 35 274

(3aα,4β,7β,7aα)-Hexahydro-4-(2-hydroxyethyl)-7-methyl-2-(3-methyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.44LC 204, 35 275

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethoxy)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.97LC 204, 35 276

CH₃(3aα,4β,7β,7aα)-2-(3,5-Dichlorophenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.31LCMS341.2[M + H]⁺ 20 277

CH₃(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.04LCMS 20 278

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(phenylmethoxy)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.4.06LC 204, 35 279

(3aα,4β,7β,7aα)-Hexahydro-4-(2-hydroxyethyl)-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.607 & 2.743rotationalisomersLC 204, 35 280

(3aα,4β,7β,7aα)-4-[2-(4-Fluorophenoxy)ethyl]hexahydro-7-methyl-2-(3-methyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.68LC 204, 35 281

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-[(trifluoromethyl)thio]phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.4.11LC 204, 35 282

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-7-[2-(4-nitrophenoxy)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.68LC 204, 35 283

(3aα,4β,7β,7aα)-4-[2-(4-Fluorophenoxy)ethyl]hexahydro-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.68 & 3.80rotationalisomersLC 204, 35 284

(3aα,4β,7β,7aα)-4-[Octahydro-7-methyl-1,3-dioxo-7-[2-[2-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.89LC 204, 35 285

(3aα,4β,7β,7aα)-4-[4-[2-(2-Bromophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.91LC 204, 35 286

(3aα,4β,7β,7aα)-4-[4-[2-(3-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.78LC 204, 35 287

H(3aα,4β,7β,7aα)-Hexahydro-2-[4-(1H-imidazol-1-yl)phenyl]-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.16LC 3 288

H(3aα,4β,7β,7aα)-2-[3-Chloro-4-(2-thiazolyl)phenyl]hexahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.81LC 3 289

CH₃(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(3-methyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.74LC 20 290

CH₃(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(2-methyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.71LC 20 291

(3aα,4β,7β,7aα)-2-(3,5-Dichlorophenyl)hexahydro-4-(2-hydroxyethyl)-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.98LC 204 292

(3aα,4β,7β,7aα)-2-(3,5-Dichlorophenyl)-4-[2-(4-fluorophenoxy)ethyl]hexahydro-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.4.03LC 204, 35 293

(3aα,4β,7β,7aα)-4-[Octahydro-4-[2-(4-hydroxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.25LC 204, 35 294

(3aα,4β,7β,7aα)-4-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.51LC 204, 35 295

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[3-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.85LC 204, 35 296

(3aα,4β,7β,7aα)-4-[4-[2-(3-Bromophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.84LC 204, 35 297

(3aα,4β,7β,7aα)-4-[4-[(4-Fluorophenyl)methyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.73LC 205 298

CH₃(3aα,4β,7β,7aα)-2-(1,6-Dihydro-1-methyl-6-oxo-3-pyridinyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole1,3(2H)-dione.1.61LC 20 299

CH₃(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(1-methyl-6-oxo-3-piperidinyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.73LC 20 300

(3aα,4β,7β,7aα)-4-[4-[2-(3-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.46LC 204, 35 301

(3aα,4β,7β,7aα)-4-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]benzoicacid,phenylmethylester. 4.01LC 204, 35 302

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(2-phenoxyethyl)-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.57LC 204, 35 303

CH₃(3aα,4β,7β,7aα)-2-(3,5-Dichloro-4-nitrophenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.40LC 20 304

CH₃(3aα,4β,7β,7aα)-2-(3,5-Dichloro-4-hydroxyphenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.58LC 20 305

CH₃(3aα,4β,7β,7aα)-2-(5-Fluoro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.96 & 3.06rotationalisomersLC 20 306

CH₃(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.60 & 2.73rotationalisomersLC 20 307

CH₃(3aα,4β,7β,7aα)-Hexahydro-2-[3-methoxy-4-(5-oxazolyl)phenyl]-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.62LC 20 308

(3aα,4β,7β,7aα)-Hexahydro-4-[2-(4-methoxyphenoxy)ethyl]-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.42 & 3.55rotationalisomersLC 204, 35 309

(3aα,4β,7β,7aα)-Hexahydro-4-methyl-2-(4-nitro-1-naphthalenyl)-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.81 & 3.93rotationalisomersLC 204, 35 310

(3aα,4β,7β,7aα)-Hexahydro-4-methyl-2-(4-nitro-1-naphthalenyl)-7-[2-(4-nitrophenoxy)ethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.48 & 3.61rotationalisomersLC 204, 35 311

CH₃(3aα,4β,7β,7aα)-2-(1,6-Dihydro-1,4-dimethyl-6-oxo-3-pyridinyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole1,3(2H)-dione.1.89LC 20 312

(3aα,4β,7β,7aα)-4-[Octahydro-7-methyl-2-(4-nitro-1-naphthalenyl)-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]benzonitrile.3.63LC 204, 35 313

CH₃(3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-1,2-benzenedicarbonitrile.2.38LC 20 314

(3aα,4β,7β,7aα)-4-(2-Bromoethyl)hexahydro-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.52LC 36 315

(3aα,4β,7β,7aα)-4-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.19 & 3.35rotationalisomersLC 223, 35 316

(3aα,4β,7β,7aα)-4-[Octahydro-4-[2-(4-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.34 & 3.50rotationalisomersLC 223, 35 317

(3aα,4β,7β,7aα)-4-[Octahydro-4-[2-(3-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.34 & 3.50rotationalisomersLC 223, 35 318

(3aα,4β,7β,7aα)-4-[4-[2-(3-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.46 & 3.61rotationalisomersLC 223, 35 319

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-7-[2-[3-(4-morpholinyl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.01 & 3.18rotationalisomersLC 223,35 320

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-7-[2-[4-nitro-3-(triflouoromethyl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.70 & 3.83rotationalisomersLC 223, 35 321

(3aα,4β,7β,7aα)-4-[4-[2-(3-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.39 & 3.55rotationalisomersLC 223, 35 322

CH₃(3aα,4β,7β,7aα)-2-(2,3-Dihydro-3-methyl-2-oxo-6-benzothiazolyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.34LC 20 323

CH₃(3aα,4β,7β,7aα)-2-(2,3-Dihydro-2-oxo-6-benzothiazolyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.16LC 20 324

(3aα,4β,7β,7aα)-4-[4-[2-[3-(Dimethylamino)phenoxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.2.63 & 2.79rotationalisomersLC 223, 35 325

(3aα,4β,7β,7aα)-4-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]-1,2-benzenedicarbonitrile.3.42LC 223, 35 326

CH₃(3aα,4β,7β,7aα)-N-[2-Cyano-5-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)phenyl]acetamide.1.94LC 20 327

CH₃(3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethoxy)benzonitrile.3.52LC 20 328

CH₃(3aα,4β,7β,7aα)-2-Methoxy-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile.2.47LC 20 329

CH₃(3aα,4β,7β,7aα)-2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.09LC 20 330

CH₃(3aα,4β,7β,7aα)-2-[4-(4-Bromo-1-methyl-1H-pyrazol-3-yl)phenyl]hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.04LC 20 331

(3aα,4β,7β,7aα)-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.2.44 & 2.60rotationalisomersLC 223 332

CH₃(3aα,4β,7β,7aα)-2-Iodo-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile.2.78LC 20 333

(3aα,4β,7β,7aα)-4-[4-[2-(4-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.39 & 3.53rotationalisomersLC 223, 35 334

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.66 & 3.78rotationalisomersLC 223, 35 335

(3aα,4β,7β,7aα)-4-[4-[2-(4-Cyano-3-fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.26 & 3.41rotationalisomersLC 223, 35 336

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.94 & 4.01rotationalisomersLC 223, 35 337

CH₃(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[4-(1H-1,2,4-triazol-3-yl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.06LC 20 338

CH₃(3aα,4β,7β,7aα)-2-[4-(4,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)phenyl]hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole1,3(2H)-dione.2.42LC 20 339

CH₃(3aα,4β,7β,7aα)-Hexahydro-2-[3-methoxy-4-(2-oxazolyl)phenyl]-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.51LC 20 340

CH₃(3aα,4β,7β,7aα)-Hexahydro-2-(4-hydroxy-1-naphthalenyl)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.30LC 20 341

CH₃(3aα,4β,7β,7aα)-Hexahydro-2-(8-hydroxy-5-quinolinyl)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione,trifluoroacetate(1:1).1.49LC 20 342

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[methyl(phenylmethyl)amino]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.2.42LC 204, 35 343

CH₃(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(5-quinolinyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.69LC 20 344

CH₃(3aα,4β,7β,7aα)-5-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-pyridinecarbonitrile.2.18LC 20 345

CH₃(3aα,4β,7β,7aα)-5-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-8-quinolinecarbonitrile.2.31LC 20 346

CH₃(3aα,4β,7β,7aα)-2-(5-Bromo-4-nitro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.10 & 3.29rotationalisomersLC 20 347

CH₃(3aα,4β,7β,7aα)-2-(5-Bromo-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.28 & 3.40rotationalisomersLC 20 348

CH₃(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[8-(trifluoromethyl)-4-quinolinyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.08LC 20 349

4-Fluorobenzoicacid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester. 3.64 & 3.77rotationalisomersLC 223 350

Benzeneaceticacid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester. 3.53 & 3.67rotationalisomersLC 223 351

4-Fluorobenzeneaceticacid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester. 3.53 & 3.66rotationalisomersLC 223 352

(3aα,4β,7β,7aα)-Hexahydro-4-methyl-7-[2-[4-(methylsulfonyl)phenoxy]ethyl]-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.31LC 204, 35 353

CH₃(3aα,4β,7β,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.94LC 20 354

CH₃(3aα,4β,7β,7aα)-2-(4-Chloro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.22 & 3.34rotationalisomersLC 20 355

(3aα,4β,7β,7aα)-N-[(4-Chlorophenyl)methyl]-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-acetamide.3.52LC 237 356

4,7,7-Trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylicacid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester. 3.45LC 223 357

(αS)-α-Methoxy-α-(trifluoromethyl)benzeneaceticacid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester. 3.91LC 223 358

(αR)-α-Methoxy-α-(trifluoromethyl)benzeneaceticacid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester. 2.00LC 223 359

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-7-[2-[(7-methyl-1,2-benzisoxazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.79 & 3.92LCRotationaleisomers 250 360

(3aα,4β,7β,7aα)-4-[4-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.55 & 3.70LCRotationaleIsomers 250 361

(3aα,4β,7β,7aα)-4-[2-(Benzoyloxy)ethyl]-2-(4-cyano-1-naphthalenyl)hexahydro-7-methyl-4,7-epoxy-1H-isoindole1,3(2H)-dione.3.51 & 3.66LCRotationaleisomers 223 362

(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)-4-[2-[(4-nitrobenzoyl)oxy]ethyl]hexahydro-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.52 & 3.67LCRotationaleIsomers 223 363

4-Chlorobenzoicacid,2-[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-y]ethylester. 3.79LC 223 364

[3aα,4β,7β,7aα(E)]-4-[Octahydro-4-methyl-7-[3-(1-naphthalenyl)-2-propenyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.4.14LC499.13[M + H]⁺ 248 365

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-7-[3-(1-naphthalenyl)propyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.4.14LC501.14[M + H]⁺ 248, 249 366

CH₃(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(2-methyl-6-quinolinyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.25LC337.0[M + H]⁺ 20 367

CH₃(3aα,4β,7β,7aα)-Hexahydro-2-(5-isoquinolinyl)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.06 & 1.29LCRotationaleIsomers323.0[M + H]⁺ 20 368

CH₃(3aα,4β,7β,7aα)-2-(6-Benzothiazolyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.15LC329.0[M + H]⁺ 20 369

[3aα,4β,7β,7aα(E)]-4-[Octahydro-4-methyl-1,3-dioxo-7-(4-oxo-4-phenyl-2-butenyl)-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.50LC477.1[M + H]⁺ 265 370

(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-N-(2-hydroxyphenyl)-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-acetamide.3.07LC482.14[M + H]⁺ 236 371

[3aα,4β(E),7β,7aα]-[Octahydro-4-methyl-7-[3-(6-methyl-2-pyridinyl)-2-propenyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.2.28LC464.19[M + H]⁺ 248 372

(3aα,4β,7β,7aα)-4-[Octahydro-4-methyl-7-[3-(6-methyl-2-pyridinyl)propyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.2.19LC466.32[M + H]⁺ 248, 249 373

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(3-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.73LC483.65[M + H]⁺ 238i, 239i 374

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(3-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.73LC 238ii, 239ii 375

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.33 & 3.49LCRotationaleIsomers 238i, 239i 376

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.73LC483.65[M + H]⁺ 238ii, 239ii 377

[3aα,4β(E),7β,7aα]-4-[4-[3-(1H-Benzimidazol-2-yl)-2-propenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.48LC489.26[M + H]⁺ 248 378

(3aα,4β,7β,7aα)-4-[4-[3-(1H-Benzimidazol-2-yl)propyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.37LC491.26[M + H]⁺ 249

EXAMPLES 379 TO 381

Additional compounds of the present invention were prepared byprocedures analogous to those described above. The compounds of Examples379 to 381 have the following structure (L is a bond):

where G, R⁷, the compound name, retention time, molecular mass, and theprocedure employed, are set forth in Table 6. The chromatographytechniques used to determine the compound retention times of Table 6 areas follows: LCMS=YMC S5 ODS column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm. LCMS*=YMC S5 ODS column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm. LC=YMC S5ODS column 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm.The molecular mass of the compounds listed in Table 6 were determined byMS (ES) by the formula m/z.

TABLE 6 Retention Time Min./ Ex. Compound Molecular Procedure No G R⁷Name Mass of Ex. 379

(3aα,4α,7α,7aα)-4-[4-[(4-Fluorophenyl)methyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile.3.75LC 205 380

CH₃(3aα,4α,7α,7aα)-Hexahydro-4,7-dimethyl-2-(1-methyl-6-oxo-3-piperidinyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.88LC 27 381

CH₃(3aα,4α,7α,7aα)-2-(1,6-Dihydro-1,4-dimethyl-6-oxo-3-pyridinyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.91LC 27

EXAMPLES 382 TO 383

Additional compounds of the present invention were prepared byprocedures analogous to those described above. The compounds of Examples382 to 383 have the structure, compound name, retention time, molecularmass, and were prepared by the procedure employed, set forth in thefollowing Table 7. The chromatography techniques used to determine thecompound retention times of Table 7 are as follows: LCMS=YMC S5 ODScolumn, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% TFA; 4 mL/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column,4.6×50 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1%TFA; 4 mL/min, monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm. The molecular mass of thecompounds listed in Table 7 were determined by MS (ES) by the formulam/z.

TABLE 7 Ex. Compound Retention Procedure No. Structure Name Time Min. ofExample 382

(3aα,4β,7β,7aα)-2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile.3.63LC 255 383

(3aα,4β,7β,7aα)-2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile3.64LC 255

EXAMPLES 384 TO 418

Additional compounds of the present invention were prepared byprocedures analogous to those described above. The compounds of Examples384 to 418 have the following structure (L is a bond):

where G, R⁷, the compound name, retention time, molecular mass, and theprocedure employed, are set forth in Table 8. The absolute configurationfor the following compounds was not determined. For simplicity innomenclature, compound 243Di is designated herein as having an “S”configuration and compound 243Dii as having an “R” configuration.Enantiomerically pure products derived from compound 243Di aredesignated herein as having an “S” configuration and enantiomericallypure products derived from compound 243Dii are designated herein ashaving an “R” configuration.

The chromatography techniques used to determine the compound retentiontimes of Table 8 are as follows: LCMS=YMC S5 ODS column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4mL/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm. The molecular mass of the compounds listed inTable 8 were determined by MS (ES) by the formula m/z.

TABLE 8 Retention Time Min./ Ex. Compound Molecular Procedure No G R⁷Name Mass of Ex. 384

(3aα,4β,7β,7aα)-4-[7-[2-(4-Cyanophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.18LC494.40[M + H]⁺ 227, 228, 229 385

[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.19LC571.3[M − H +OAc]⁻ 243Di, 244i 386

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.22LC571.2[M − H +OAc]⁻ 234Dii, 244ii 387

[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.37LC562.2[MH + OAc]⁻ 243Di, 244i 388

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.37LC504.0[M + H]⁺ 243Dii, 244ii 389

[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-(4-Chlorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.51LC503.08[M + H]⁺ 243Di, 244i 390

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-(4-Chlorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.51LC503.08[M + H]⁺ 243Dii, 244ii 391

[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-(4-Acetylphenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.05LC511.13[M + H]⁺ 243Di, 244i 392

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-(4-Acetylphenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.05LC503.13[M + H]⁺ 243Dii, 244ii 393

[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-(3-Cyanophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.09LC494.13[M + H]⁺ 243Di, 244i 394

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-(3-Cyanophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.09LC494.13[M + H]⁺ 243Dii, 244ii 395

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.85LC523.17[M + H]⁺ 243Di, 244i 396

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.85LC523.17[M + H]⁺ 243Dii, 244ii 397

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.29LC537.13[M + H]⁺ 243Di, 244i 398

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.29LC537.13[M + H]⁺ 243Dii, 244ii 399

[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-(4-Fluorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.28LC487.11[M + H]⁺ 243Di, 244i 400

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-(4-Fluorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.27LC487.11[M + H]⁺ 243Dii, 244ii 401

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(4-methyl-2-oxo-2H-1-benzopyran-7-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.15LC551.15[M + H]⁺ 243Di, 244i 402

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(4-methyl-2-oxo-2H-1-benzopyran-7-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.16LC551.10[M + H]⁺ 243Dii, 244ii 403

[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-(3,5-Dimethoxyphenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.28LC529.19[M + H]⁺ 243Di, 244i 404

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-(3,5-Dimethoxyphenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.26LC529.12[M + H]⁺ 243Dii, 244ii 405

[3aR-(3aα,4β,7β,7aα)]-]-4-[7-[2-(4-Chloro-3-methylphenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.68LC517.33[M + H]⁺ 243Dii, 244ii 406

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-(4-Cyano-2,3-difluorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.23LC530.13[M + H]⁺ 243Dii, 244ii 407

[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.59LC602.1[M − H +OAc]⁻ 243Di, 252 408

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.3.57LC602.0[M − H +OAc]⁻ 243Dii, 253 409

[3aR-(3aα,4β,7β,7aα)]-3-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-6-hydroxy-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]-5-isoxazolecarboxylicacid,methyl ester. 2.90LC518.27[M + H]⁺ 243Dii, 253 410

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[4-(1H-1,2,4-triazol-1-yl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile.2.93LC536.30[M + H]⁺ 243Dii, 244ii 411

[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-[(7-Chloro-4-quinolinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1). 2.52LC554.13[M + H]⁺ 243Di, 244i 412

[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-[(7-Chloro-4-quinolinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1). 2.53LC554.27[M + H]⁺ 243Dii, 244ii 413

[3aR-(3α,4β,5β,7β,7aα)]-4-[7-[2-(2-Benzoxazolyloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.13LC568.1[MH + OAc]⁻ 243Dii, 244ii 414

[3aR-(3α,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(9-methyl-9H-purin-8-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.34LC525.2[M + H]⁺ 243Dii, 244ii 415

[3aR-(3α,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(1-methyl-1H-indazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.33LC 251, 253 416

[3aS-(3α,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[4-(1,2,3-thiadiazol-5-yl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.17LC553.10[M + H]⁺ 243Dii, 244ii 417

[3aR-(3α,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[4-(1,2,3-thiadiazol-5-yl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.20LC553.25[M + H]⁺ 243Dii, 244ii 418

[3aS-(3α,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.45LC538.23[M + H]⁺ 243Dii, 244ii 419

[3aR-(3α,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.45LC538.23[M + H]⁺ 243Dii, 244ii 420

[3aS-(3α,4β,5β,7β,7aα)]-4-[7-[2-[(6-Chloro-2-methyl-4-pyrimidinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.02LC 243Dii, 244ii 421

[3aR-(3α,4β,5β,7β,7aα)]-4-[7-[2-[(6-Chloro-2-methyl-4-pyrimidinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.02LC 243Dii, 244ii

EXAMPLE 422(3aα,4β,7β,7aα)-2-(7-Bromo-2,1,3-benzoxadiazol-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(422C)

A. 4-Bromo-7-nitrobenzofurazan (422A)

To a solution of 2,6-dibromoaniline (1.0 g, 4.0 mmol) in CHCl₃ (8 mL)was added a suspension of mCPBA (70% by HPLC, 1.4 g, 8.0 mmol) in CHCl₃(8 mL) and the resulting mixture was stirred for 24 h at rt. Thereaction mixture was diluted with CHCl₃ and washed successively with 2%Na₂S₂O₃ solution, 5% Na₂CO₃ solution and brine. The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to leave asolid, which was suspended, into DMSO (15 mL). To this suspension wasadded a solution of NaN₃ (272 mg, 4.19 mmol) in DMSO (15 mL) at rt. Theresulting mixture was stirred at rt until most of the nitrogen hadevolved and was then quickly heated to 120° C. for 3 min. The reactionmixture was cooled and poured onto crushed ice (100 g). After standingfor 1 h the precipitates were filtered off, dried in vacuo andredissolved in conc. H₂SO₄ (5 mL). To this solution was added a solutionof NaNO₃ (400 mg, 4.7 mmol) in 50% H₂SO₄ (1.6 mL) and the temperaturewas maintained at 60° C. After the addition was complete, the mixturewas heated at 85° C. for 30 min, cooled to rt and poured onto crushedice (40 g). EtOAc was added, the layers were separated and the aqueouslayer was extracted with EtOAc. The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure to leave a solidwhich was purified by flash chromatography (silica gel, EtOAc (20%) inhexanes) affording compound 422A (785 mg, 81%) as a tan solid.

B. 4-Bromo-7-aminobenzofurazan (422B)

A solution of compound 422A (563 mg, 2.31 mmol) in AcOH (5 mL) washeated to 70° C. and Fe⁰ powder (258 mg, 4.62 mmol) was added in oneportion. The resulting dark reaction mixture was stirred for 15 min,cooled to rt and concentrated under reduced pressure. The residue wastaken up in EtOAc and the resulting solution was washed with sat. Na₂CO₃solution. The organic layer was dried over Na₂SO₄, concentrated in vacuoand purified by flash chromatography on silica gel eluting with 10-60%EtOAc in hexanes to give 470 mg (95%) of compound 422B as a red solid.

C.(3aα,4β,7β,7aα)-2-(7-Bromo-2,1,3-benzoxadiazol-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(422C)

A mixture of compound 422B (43 mg, 0.20 mmol), compound 20A (45 mg, 0.23mmol), MgSO₄ (60 mg, 0.50 mmol), Et₃N (139 μL, 1.0 mmol) and1,2-dimethoxyethane (300 μL) were placed in a sealed tube and heated at135° C. for 14 h. After cooling to rt the mixture was filtered throughCelite eluting with MeOH to yield a dark solid which was purified byflash chromatography on silica gel eluting with 5-40% EtOAc in hexanesto give 42 mg (54%) of compound 422C as a yellow solid. HPLC: 99% at2.96 min (retention time) (YMC S5 ODS column 4.6×50 mm Ballistic, 10-90%aqueous methanol over 4 minutes containing 0.2% H₃PO₄, 4 mL/min,monitoring at 220 nm). ¹H NMR (acetone-d₆, 400 MHz): δ=8.00 (d, J=7.5Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 3.31 (s, 2H), 1.98-1.93 (m, 2H),1.74-1.69 (m, 2H), 1.57 (s, 6H).

EXAMPLE 423(3aα,4β,7β,7aα)-7-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzoxadiazole-4-carbonitrile(423)

To a solution of compound 422C (42 mg, 0.11 mmol) in DMA (1 mL) wasadded CuCN (20 mg, 0.22 mmol) and the resulting mixture was heated at150° C. for 5 h. The mixture was allowed to cool to rt and partitionedbetween EtOAc and aqueous NaCN solution (5 g/50 mL). The layers wereseparated and the aqueous layer was extracted once with EtOAc. Thecombined organic phases were dried over Na₂SO₄, concentrated in vacuoand purified by flash chromatography on silica gel eluting with 20-70%EtOAc in hexanes to give 13 mg (35%) of compound 423 as a yellow. oil.HPLC: 99% at 2.66 min (retention time) (YMC S5 ODS column 4.6×50 mmBallistic, 10-90% aqueous methanol over 4 minutes containing 0.2% H₃PO₄,4 mL/min, monitoring at 220 nm). MS (ES): m/z 396.9 [M−H+OAc]⁻.

EXAMPLE 424(3aα,4β,7β,7aα)-7-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(424B)

A. 4-Cyano-7-amino-benzothiadiazole (424A)

A solution of 2-cyano-5-nitrophenylenediamine (78 mg, 0.44 mmol,prepared as described in WO 0076501) in SOCl₂ (2 mL) was heated toreflux for 3 h. The resulting mixture was allowed to cool to rt and wasthen poured into ice/water. CH₂Cl₂ was added, the layers were separatedand the aqueous layer was extracted twice with CH₂Cl₂. The combinedorganic phases were dried over MgSO₄, concentrated in vacuo and purifiedby flash chromatography on silica gel eluting with 50% EtOAc in hexanesto give 4-cyano-7-nitrobenzothiadiazole. This material was dissolved inAcOH (2 mL) containing EtOAc (1 mL) and H₂O (0.2 mL) and heated to 70°C. At this temperature Fe⁰ powder (78 mg, 1.41 mmol) was added in onesolid portion and the dark mixture was stirred for 20 min and thencooled to rt. The reaction mixture was filtered through Celite elutingwith EtOAc, washed with sat. Na₂CO₃ solution, dried over MgSO₄ andconcentrated in vacuo. Purification by flash chromatography on silicagel eluting with 20-70% EtOAc in hexanes to yield 47 mg (67%) ofcompound 424A as a brown solid.

B.(3aα,4β,7β,7aα)-7-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(424B)

A mixture of compound 424A (35 mg, 0.20 mmol), compound 20A (45 mg, 0.23mmol), MgSO₄ (60 mg, 0.50 mmol), Et₃N (139 μL, 1.0 mmol) and DME (200μL) was placed in a sealed tube and heated at 135° C. for 14 h. Aftercooling to rt the mixture was filtered through Celite eluting with MeOHto yield a dark solid which was purified by a combination of flashchromatography on silica gel eluting with 10-50% EtOAc in hexanesreverse phase preparative HPLC (YMC S5 ODS 20×100 mm eluting with27-100% aqueous methanol over 10 mincontaining 0.1% TFA, 20 mL/min) togive 36 mg (51%) of compound 424B as a yellow solid. HPLC: 98% at 2.45min (retention time) (YMC S5 ODS column 4.6×50 mm Ballistic, 10-90%aqueous methanol over 4 minutes containing 0.2% H₃PO₄, 4 mL/min,monitoring at 220 nm). MS (DCI): m/z 355.0 [M+H]⁺.

EXAMPLE 425(3aα,4β,7β,7aα)-N-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]-4-fluoro-N-methylbenzamide(425B)

A. 4-Fluoro-N-methyl-N-[2-(5-methyl-furan-2-yl)-ethyl]-benzamide (425A)

NaH (60% dispersion in oil, 65 mg, 1.63 mmol) was added portionwise to asolution of 4-fluoro-N-[2-(5-methyl-2-furanyl)ethyl]benzamide (269 mg,1.09 mmol, 237A) in THF (5 mL). After gas evolution ceased, iodomethane(0.14 mL, 2.18 mmol) was added drop-wise. Once HPLC analysis showed thereaction to be 50% complete, the mixture was concentrated under reducedpressure and resubjected to the above conditions. After all the startingmaterial was consumed, H₂O was added and the resulting mixture wasextracted with EtOAc (2×5 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. Purification byflash chromatography on silica gel eluting with 20% acetone/CHCl₃ gave238 mg (84%) of compound 425A. HPLC: 98% at 2.94 min (retention time)(Phenomenex-prime S5-C18 column 4.6×50 mm eluting with 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z [M+H]=262.38.

B. (3aα,4β,7β,7aα)-N-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-25methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethyl]-4-fluoro-N-methylbenzamide(425B)

A solution of compound 425A (183 mg, 0.75 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (174 mg,0.75 mmol) in benzene (1 mL) was heated at 60° C. for 15 hr. Thereaction mixture was concentrated under reduced pressure to give 357 mgcrude intermediate. The crude intermediate (156 mg) was dissolved inEtOAc (6 mL) and 10% Pd/C (16 mg) was added and the mixture was stirredunder a hydrogen balloon overnight. The reaction mixture was filteredthrough a pad of Celite and concentrated under reduced pressure.Purification by reverse phase preparative HPLC (YMC S5 ODS 20×100 mm,20-100% aqueous methanol over 15 minutes containing 0.1% TFA, 20 mL/min,monitoring at 220 nm) gave 160.3 mg (72%) of compound 425B as anoff-white solid. HPLC: 99% at 3.23 min (retention time)(Phenomenex-prime S5-C18 column 4.6×50 mm eluting with 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z [M+H]=512.19.

EXAMPLE 426(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(426B)

A. 1-(4-Amino-phenyl)-2,2,2-trifluoro-ethanol (426A)

Compound 426A was made according to the procedure described in Stewart,R. et al. Can. J. Chem. 58, 2491-2496 (1980). NaBH₄ (47 mg, 1.235 mmol)was added to a solution of p-aminotrifluoroacetophenone (155.7 mg, 0.823mmol, synthesized as described by Klabunde, K. J. et al. J. Org. Chem.35, 1711-1712 (1970)) in isopropanol (3 mL) at rt. After 30 min thereaction was quenched with phosphate buffer (pH 7.2), diluted with H₂Oand extracted with EtOAc (2×10 mL). The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure to give 154 mg(98%) of compound 426A as a tan solid. The material was used directly inthe next step without purification. HPLC: 99% at 0.42 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). MS (ES): m/z [M+H]=192.13.

B.(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(426B)

A mixture of compound 426A (75.3 mg, 0.394), compound 20A (51.5 mg,0.262 mmol), triethylamine (0.15 mL) and MgSO₄ (50 mg) in toluene (1 mL)was heated in a sealed tube to 135° C. for 15 hr. The mixture wasfiltered and concentrated under reduced pressure. Purification byreverse phase preparative HPLC (YMC S5 ODS 20×100 mm, 20-100% aqueousmethanol over 15 minutes containing 0.1% TFA, 20 mL/min, monitoring at220 nm) gave 63.1 mg (65%) of compound 426B as a white solid. HPLC: 98%at 2.49 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z[M+H]=370.16.

EXAMPLE 427(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-1,3,3a,4,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile&(3aα,4α,7α,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-1,3,3a,4,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(427i & 427ii)

Compound 204A (2.00 g, 8.50 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(1.50 g, 5.60 mmol) were mixed in benzene (5.0 mL) and heated at 60° C.for 14 h, then cooled to 25° C. The solvent was removed at 40° C. undervacuum for 1 h to give the crude material which was purified by flashchromatography on SiO₂ eluting with 0.5% EtOAc/CH₂Cl₂ to give 2.0 g ofcompound 427i and 1.3 g of compound 427ii, both as light brown solids.Compound 427i: HPLC: 95% at 4.200 min (retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 507.1 [M+H]⁺. Compound 427ii: HPLC: 95% at 4.20 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at220 nm). MS (ES): m/z 507.1 [M+H]⁺.

EXAMPLE 428[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile&[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-Dimethylethlyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(428i & 428ii)

Compound 427i (1.40 g, 2.77 mmol) and RhCl(PPh₃)₃ (0.128 g, 0.14 mmol)were mixed in a flask. The flask was then evacuated and filled withargon three times, followed by the syringe addition of THF (3.0 mL).Once all particulates were dissolved, catecholborane (0.59 mL, 5.54mmol) was added dropwise. The reaction mixture was stirred at 25° C.under argon for 30 min, then cooled to 0° C. Phosphate buffer (pH 7, 20mL) was added, followed by EtOH (10 mL), 30% H₂O₂/H₂O (2 mL). Thereaction mixture was stirred at 0° C. for 3 h, then extracted withdichloromethane (3×25 mL). The combined organic layers were washed with1 N NaOH (25 mL), 10% Na₂SO₃ (25 mL) and brine (25 mL). The crudematerial was then concentrated in vacuo and purified by flashchromatography on SiO₂ eluting with 2% EtOAc/CH₂Cl₂ to 10% EtOAc/CH₂Cl₂to give 0.63 g of a racemic mixture of compounds 428i & 428ii as a lightyellow solid. HPLC: 99% at 3.867 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z525.1 [M+H]

The racemic mixture of compounds 428i & 428ii was separated by normalphase preparative chiral HPLC using a Chiracel OD column (5 cm×50 cm),eluting with 13% solvent B (EtOH) in solvent A (hexanes), flow rate: 50mL/min. Compound 428i eluted from 34 min to 38 min and compound 428iieluted from 44 min to 49 min. Enantiomeric excess was determined bychiral HPLC. Compound 428i: >99% ee (12.576 min (retention time)(Chiralcel OJ column 4.6×250 mm eluting with isocratic 85% heptane/15%MeOH/ethanol (1:1), 1 mL/min, monitoring at 220 nm, 40° C.). Compound428ii: 99% ee (18.133 min (retention time) (Chiralcel OJ column 4.6×250mm eluting with isocratic 85% heptane/15% MeOH/ethanol (1:1), 1 mL/min,monitoring at 220 nm, 40° C.).

The absolute configurations for compounds 428i & 428ii were notestablished. For simplicity in nomenclature, compound 428i is designatedherein as having an “R” configuration and compound 428ii as having an“S” configuration. Enantiomerically pure products derived from compound428i are designated herein as having a “R” configuration andenantiomerically pure products derived from compound 428ii aredesignated herein as having an “S” configuration.

EXAMPLE 429[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile&[3aS-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(429i & 429ii)

Compound 428i (180 mg, 0.34 mmol) was dissolved in 2% HCl/EtOH (5.0 mL).After 30 min, saturated NaHCO₃ was added and the aqueous layer wasextracted with dichloromethane (20 mL×3), washed with brine and driedover Na₂SO₄ to give 135 mg of compound 429i as a white solid. HPLC: 99%at 2.257 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm). MS (ES): m/z 411.1 [M+H]⁺.

The above procedure was repeated with compound 428ii to yield thedesired diol compound 429ii in similar yield.

EXAMPLE 430[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(430)

Triphenylphosphine (0.026 g, 0.098 mmol) and DBAD (0.023 g, 0.098 mmol)were mixed in THF (0.5 mL). After allowing the previous mixture to reactfor 15 min, 2-hydroxy-6-chloropyridine (0.016 g, 0.100 mmol) was added,the mixture was allowed to stir for 10 min and compound 429i (0.020 g,0.049 mmol) was added. The reaction mixture was stirred at 25° C. for 2h and then the crude material was purified by preparative TLC, elutingwith 10% acetone/CHCl₃, to give 0.014 g of compound 430 as a light brownsolid. HPLC: 100% at 3.370 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 522.08 [M+H]⁺.

EXAMPLE 431[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(431)

Triphenylphosphine (0.026 g, 0.098 mmol) and DBAD (0.023 g, 0.098 mmol)were mixed in THF (0.5 mL). After allowing the previous mixture to reactfor 15 min, 2-hydroxy-6-chloropyridine (0.016 g, 0.100 mmol) was added,the mixture was allowed to stir for 10 min and compound 429ii (0.020 g,0.049 mmol) was added. The reaction mixture was stirred at 25° C. for 2h and then the crude material was purified by preparative TLC, elutingwith 10% acetone/CHCl₃, to give 0.015 g of compound 431 as a light brownsolid. HPLC: 100% at 3.370 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 522.08 [M+H]⁺.

EXAMPLE 432(3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-N-(2-hydroxyphenyl)-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-butanamide(432)

Compound 262 (0.100 g, 0.239 mmol) was dissolved in DMF (anhydrous, 1.5mL), BOP (0.211 g, 0.478 mmol) was added followed by 2-aminophenol(0.052 g, 0.478 mmol) and N-methyl morpholine (0.052 mL, 0.478 mmol).The reaction mixture was stirred at 25° C. under argon for 3 h, then thecrude material was purified by reverse phase preparative HPLC (YMC S5ODS 20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1%TFA, 20 mL/min, monitoring at 220 nm) to give 0.060 g of compound 432 asa light brown solid. HPLC: 100% at 3.037 min (retention time) (YMC S5ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z510.34 [M+H]⁺.

EXAMPLE 433(3aα,4β,7β,7aα)-4-[4-[3-(2-Benzoxazolyl)propyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(433)

Triphenylphosphine (0.031 g, 0.118 mmol) and DBAD (0.027 g, 0.118 mmol)were mixed in THF (0.5 mL). After allowing the previous mixture to reactfor 15 min, compound 432 (0.030 g, 0.059 mmol) was added. The reactionmixture was stirred at 25° C. for 2 h and then the crude material waspurified by reverse phase preparative HPLC (YMC S5 ODS 20×100 mm,20-100% aqueous methanol over 15 minutes containing 0.1% TFA, 20 mL/min,monitoring at 220 nm) to give 0.018 g of compound 433 as a light brownsolid. HPLC: 100% at 3.357 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 492.37 [M+H]⁺.

EXAMPLE 434(3aα,4β,5β,7β,7aα)-4-[4-Ethyloctahydro-5-hydroxy-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(434C)

A. tert-Butyl-[2-(5-ethyl-furan-2-yl)-ethoxy]-dimethyl-silane (434A)

Imidazole (255 mg, 3.75 mmol) and TBSCl (414 mg, 2.75 mmol) were addedto the solution of 245A (350 mg, 2.5 mmol) in DMF (4 mL). The mixturewas stirred at rt for 15 hr and then 100 mg (0.66 mmol) of additionalTBSCl was added to drive the reaction to completion. After stirring foran additional hour, the reaction mixture was diluted with diethylether(100 mL) and washed with water (20 mL), 1 N HCl (20 mL), water (20 mL)and brine (20 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to give 509 mg of compound 434A(80.3%) as a yellow oil.

B.(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)-dimethylsilyl]oxy]ethyl]-4-ethyl-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(434B)

A solution of compound 434A (509 mg, 2.00 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (498 mg,2.00 mmol) in benzene (2 mL) was heated at 60° C. for 18 h. The reactionmixture was concentrated under reduced pressure to give 992 mg (99%) ofcrude compound 434B, which was used directly in the next step withoutfurther purification.

C.(3aα,4β,5β,7β,7aα)-4-[7-[2-[[(1,1-Dimethylethyl)-dimethylsilyl]oxy]ethyl]-4-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(434C)

A mixture of compound 434B (992 mg, 1.98 mmol) and RhCl₂(PPh₃)₃ (183 mg,0.198 mmol) was evacuated and filled with argon (3×). THF (20 mL) wasadded and once all particulates had dissolved, catecholborane (0.42 mL,3.96 mmol) was slowly added dropwise. When the formation of productceased, as was determined by HPLC, the reaction mixture was cooled to 0°C. and quenched with phosphate buffer (34 mL, pH 7.2) followed by theaddition of EtOH (19 mL) and 30% H₂O₂ (2.9 mL). After 2 h, additionalphosphate buffer (6.8 mL, pH 7.2), EtOH (3.8 mL) and H₂O₂ (0.6 mL) wereadded. The reaction mixture was stirred at rt for 3 h. Once the boronateintermediate was consumed, the mixture was extracted with CH₂Cl₂ (300mL) and the combined organic layers were washed with 1 N NaOH, 10% aq.NaHSO₃ and brine and then dried over Na₂SO₄. Purification by flashchromatography on silica gel eluting with 10% MeOH/CH₂Cl₂ gave 75 mg(9.3%) of compound 434C as a gray solid. HPLC conditions: 97% at 2.43min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm, 10%-90%aqueous methanol over 4 minute gradient with 0.2% H₃PO₄, detecting at220 nm). MS (ES): m/z 407.18 [M+H]⁺.

D.(3aα,4β,5β,7β,7aα)-4-[4-Ethyloctahydro-5-hydroxy-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(434D)

Compound 434C (24 mg, 0.046 mmol) was dissolved in 2% conc. HCl/EtOH(0.8 mL) and the mixture was stirred at rt for 20 min. Cold sat. NaHCO₃was added to the mixture until the solution was basic (pH 8). Thereaction was extracted with EtOAc (3×2 mL) and the combined organiclayers were washed with brine (2×5 mL) and dried over anhydrous sodiumsulfate. Concentration in vacuo gave 14 mg (75%) of compound 434D as awhite solid. HPLC: 95% at 2.40 min (retention time) (YMC S5 ODS 4.6×50mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2% H₈PO₄,monitoring at 220 nm).

EXAMPLE 435(3aα,4β,5β,7β,7aα)-4-[7-[2-(4-Cyanophenoxy)ethyl]-4-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(435)

DBAD (39.6 mg, 0.172 mmol) was added to a solution of PPh₃ (45.1 mg,0.172 mmol) in THF (0.8 mL). After stirring for 10 min, 4-cyanophenol(20.5 mg, 0.172 mmol) was added and the reaction mixture was stirred foran additional 5 min. Compound 434C (25.0 mg, 0.062 mmol) was added andthe mixture was stirred at rt for 2 h. The reaction was concentratedunder reduced pressure. Purification by Prep TLC eluting with 10%acetone/CHCl₃ gave 18.1 mg (0.036 mmol, 57.6%) of compound 435. HPLCconditions: 96% at 3.15 min (retention time) (YMC S5 ODS 4.6×50 mm,10%-90% aqueous methanol over 4 minute gradient with 0.2% H₃PO₄,detecting at 220 nm). MS (ES): m/z 508.14 [M+H]⁺.

EXAMPLE 436 (3aα,4β,7β,7aα)-2-(4-Cyano-1-naphthyalenyl)octahydro-N-(2-hydroxyphenyl)-7-methyl-1,3-dioxo-4,7-expoxy-4H-isoindole-4-ethanamide(436)

Compound 234B (0.100 g, 0.256 mmol) was dissolved in DMF (anhydrous, 1.5mL), BOP (0.225 g, 0.51 mmol) was added followed by 2-aminophenol (0.056g, 0.51 mmol) and N-methyl morpholine (0.056 mL, 0.51 mmol). Thereaction mixture was stirred at 25° C. under argon for 3 h, then thecrude material was purified by reverse phase preparative HPLC (YMC S5ODS 20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1%TFA, 20 mL/min, monitoring at 220 nm) to give 0.078 g of compound 436 asa light brown solid. HPLC: 100% at 3.037 min (retention time) (YMC S5ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z482.34 [M+H]⁺.

EXAMPLE 437(3aα,4β,7β,7aα)-4-[4-(2-Benzoxazolylmethyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(437)

Triphenylphosphine (0.082 g, 0.312 mmol) and DBAD (0.072 g, 0.312 mmol)were mixed in THF (0.5 mL). After allowing the previous mixture to reactfor 15 min, compound 436 (0.075 g, 0.156 mmol) was added. The reactionmixture was stirred at 25° C. for 2 h and then the crude material waspurified by reverse phase preparative HPLC (YMC S5 ODS 20×100 mm,20-100% aqueous methanol over 15 minutes containing 0.1% TFA, 20 mL/min,monitoring at 220 nm) to give 0.052 g of compound 437 as a light brownsolid. HPLC: 100% at 3.443 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 464.18 [M+H]⁺.

EXAMPLE 438(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(438)

A mixture of 2-(4′-aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (95.7mg, 0.369), compound 20A (48.3 mg, 0.246 mmol), triethylamine (0.15 mL)and MgSO₄ (50 mg) in toluene (1 mL) was heated in a sealed tube to 135°C. overnight. The mixture was filtered and concentrated under reducedpressure. Purification by reverse phase preparative HPLC (YMC S5 ODS20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1% TFA,20 mL/min, monitoring at 220 nm) gave 44.0 mg (41%) of compound 438 as awhite solid. HPLC: 99% at 3.10 min (retention time) (Phenomenex-primeS5-C18 column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ES): m/z [M+H]=438.14.

EXAMPLES 439 TO 454

Additional compounds of the present invention were prepared byprocedures analogous to those described above. The compounds of Examples439 to 454 have the following structure (L is a bond):

where G, R⁷, the compound name, retention time, molecular mass, and theprocedure employed, are set forth in Table 9. The absolute configurationfor the following compounds was not determined. For simplicity innomenclature, compound 243Di is designated herein as having an “S”configuration and compound 243Dii as having an “R” configuration.Enantiomerically pure products derived from compound 243Di aredesignated herein as having an “S” configuration and enantiomericallypure products derived from compound 243Dii are designated herein ashaving an “R” configuration. Similarly, compound 428i is designatedherein as having an “S” configuration and compound 428ii as having an“R” configuration. Enantiomerically pure products derived from compound428i are designated herein as having an “S” configuration andenantiomerically pure products derived from compound 428ii aredesignated herein as having an “R” configuration.

The chromatography techniques used to determine the compound retentiontimes of Table 9 are as follows: LCMS=YMC S5 ODS column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4mL/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm. The molecular mass of the compounds listed inTable 9 were determined by MS (ES) by the formula m/z.

TABLE 9 Retention Time Min./ Ex. Compound Molecular Procedure No G R⁷Name Mass of Ex. 439

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(1-methyl-1H-indazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.33LC523.3[M + H]⁺ 251, 253 440

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(9-methyl-9H-purin-8-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.34LC525.2[M + H]⁺ 251, 253 441

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[1-(phenylmethyl)-1H-indazol-3-yl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.73LC 251, 253 442

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[1-(phenylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.37LC 251, 253 443

[3aS-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.45LC538.23[M + H]⁺ 243Di, 244i 444

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.46LC538.24[M + H]⁺ 243Dii, 244ii 445

[3aR-(3aα,4β,5β,7β,7aα)]-N-[4-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-7H-isoindol-7-yl]ethoxy]phenyl]acetamide2.747LC526.28[M + H]⁺ 243Dii, 244ii 446

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(2,4-Dichlorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.71LC537.17[M + H]⁺ 243Dii, 244ii 447

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[3,5-Bis(trifluoromethyl)phenoxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.89LC605.25[M + H]⁺ 243Dii, 244ii 448

[3aS-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[4-(1,2,3-thiadiazol-5-yl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.14LC553.1[M + H]⁺ 243Di, 244i 449

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[4-(1,2,3-thiadiazol-5-yl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.15LC553.23[M + H]⁺ 243Dii, 244ii 450

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5,7-Dichloro-8-quinolinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1)3.70LC588.26[M + H]⁺ 243Dii, 244ii 451

[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(4-Cyanophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile3.087LC512.13[M + H]⁺ 431 452

[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile3.563LC562.08[M + H]⁺ 431 453

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile3.57LC562.08[M + H]⁺ 430 454

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(4-Cyanophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile3.087LC512.08[M + H]⁺ 430

EXAMPLES 455 TO 457

Additional compounds of the present invention were prepared byprocedures analogous to those described above. The compounds of Examples455 to 457 have the following structure (L is a bond):

where G, R⁷, the compound name, retention time, molecular mass, and theprocedure employed, are set forth in Table 10. The absoluteconfiguration for the following compounds was not determined. Forsimplicity in nomenclature, compound 238i is designated herein as havingan “R” configuration and compound 238ii as having an “S” configuration.Enantiomerically pure products derived from compound 238i are designatedherein as having an “R” configuration and enantiomerically pure productsderived from compound 238ii are designated herein as having an “S”configuration.

The chromatography techniques used to determine the compound retentiontimes of Table 10 are as follows: LCMS=YMC S5 ODS column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4mL/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm. The molecular mass of the compounds listed inTable 10 were determined by MS (ES) by the formula m/z.

TABLE 10 Retention Procedure Ex. Compound Time Min./ of No G R⁷ NameMolecular Mass Ex. 455

(3aα,4β,5β,7β,7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(4-oxo-4-phenylbutyl)-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.53LC479.35[M + H]⁺ 265, 266 456

(3aα,4β,5β,7β,7aα)-4-[Octahydro-4-methyl-7-[3-[5-(1-methylethyl)-2-oxazolyl]propyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.547LC484.28[m + H]⁺ 248, 249 457

[3aα,4β,5β,7β,7aα(E)]-4-[Octahydro-4-methyl-7-[3-[5-(1-methylethyl)-2-oxazolyl]-2-propenyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.66LC482.28[M + H]⁺ 248, 249

EXAMPLE 458(3aα,4β,5β,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(221B & 222D)

Compound 20B was converted to compounds 221B and 222D (also synthesizedas compounds 221B and 222D) by biotransformation.

Compound 20B was hydroxylated by Amycolatopsis orientalis (ATCC 43491).A 1 mL culture from a frozen vial was used to inoculate 100 mL medium ina 500 mL portion Erlenmeyer flask and the flask was incubated at 28° C.,at 200 rpm for 3 days. A 10 mL portion of this culture was used toinoculate 100 mL medium in a 500 mL Erlenmeyer flask and the flask wasincubated at 28° C., at 200 rpm for 1 day. 10 mL portions of the 1-dayculture were distributed to each of three 50 mL flasks. Compound 20B (3mg in 0.1 mL methanol) was added to each culture and the incubationswere continued for 3 days. The culture broth in each flask was extractedwith 20 mL ethyl acetate, and the pooled ethyl acetate extracts wereevaporated to dryness at 40° C. under a nitrogen stream. The residue wasdissolved in 1.2 mL methanol and analyzed by HPLC, LC/MS and LC/NMR. Thesolution contained 2.5 mg of remaining Compound 20B, 1.6 mg of compound221B, and 1.3 mg of compound 222D. MS and NMR analyses were in agreementwith the structures shown above.

Medium: 0.5% toasted nutrisoy, 2% glucose, 0.5% yeast extract, 0.5%K₂HPO₄, 0.5% NaCl, adjusted to pH 7 with HCl (R. V. Smith and J. P.Rosazza, Arch. Biochem. Biophys., 161, 551-558 (1974)

HPLC Analysis

Column: Phenomenex Luna C18, 150×2 mm, 5μ

mobile phase: solvent A: 95% 20 mM ammonium acetate pH 5.1, 5%acetonitrile

solvent B: 95% acetonitrile, 5% 20 mM ammonium acetate pH 5.1 lineargradient going from 100% solvent A to 5% solvent A in 25 minutesfollowed by equilibration at 100% solvent A for 8 minutes.

temperature: 40° C.

detection: 250 nm

injection volume: 1 μL

retention times: compound 20B, 20.8 min; compound 221B, 16.5 min;compound 222D, 17.8 min

HPLC Conditions

Chiral HPLC conditions were employed for the separation of enantiomersand achiral HPLC conditions were employed for the separation ofdiastereomers of the hydroxylated analogs of compound 20B (i.e.,compounds 221B and 222D and compounds 254i and 254ii)

Two methods were used under chiral HPLC conditions, reverse phase (RP)for chiral analysis of biotransformation products in biological samplesand normal phase (NP) for non-biological samples.

Chiral RP-HPLC Condition

Column: CHIRALPAK AD-R 4.6 × 250 mm, 10μ Temperature: 40° C. InjectionVolume: 5 or 20 μL Mobile Phase: A: MeCN B: H₂O Isocratic, 30% of A, 18min. Flow Rate: 1 mL/min. UV Detection: 242 nmChiral NP—HPLC Condition

Column: CHIRALPAK AD 4.6 × 250 mm, 10μ Temperature: 25° C. InjectionVolume: 5 or 20 μL Mobile Phase: A: Heptane B: MeOH/Ethanol (1:1)Isocratic, 80% of A, 20 min. Flow Rate: 1 mL/min. UV Detection: 242 nm

Under these conditions compounds 254i and 254ii had retention times of8.5 minutes and 9.85 minutes, respectively.

Reverse phase HPLC was employed for the separation of the diastereomericcompounds 221B and 222D:

Mobile Phase:

-   -   Solvent A: 95% 20 mM ammonium acetate pH 5.1, 5% acetonitrile    -   Solvent B: 95% acetonitrile, 5% 20 mM ammonium acetate pH 5.1        Gradient:    -   Linear gradient going from 100% solvent A to 5% solvent A in 25        minutes followed by equilibration at 100% solvent A for 8        minutes. Total run time of 36 minutes.        Flow Rate:    -   0.2 mL/min        Column:    -   Phenomenex Luna 5 micron C₁₈ 150×2.0 mm id        Detection:    -   UV detection at 242 nm

Under these conditions, compounds 221B and 222D had retention times of18.983 min and 20.362 min, respectively.

EXAMPLE 459(3aα,4β,5β,7β,7aα)-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(459)

Compounds 223A and 331 were converted to compound 459 bybiotransformation.

Microbial hydroxylation of compound 223A

1. Reaction

To a 500 mL flask containing 100 mL of the transformation medium wasadded one frozen vial (approximately 2 mL) of Streptomyces griseus ATCC10137. The transformation medium was prepared as follows: to a 2 Lplastic beaker was added 20 g of dextrose, 5.0 g of yeast extract, 5.0 gof soybean meal, 5.0 g of sodium chloride, 5.0 g of potassium phosphate(diabasic) and 1 L of deionized water, and the mixture was stirred atroom temperature for 3 to 30 min. The pH of the mixture was thenadjusted to 7.0 with 1 N HCl or 1 N NaOH. The resulting mixture wasdispensed into 500 mL flasks (100 mL per flask). The flasks were coveredwith Bio/Wrap and autoclaved at 121° C. for 15 min. and cooled down toroom temperature before use.The culture was incubated at 28° C. and at 250 rpm for 24 hours. Ten mLof the resulting culture was transferred to a 50 mL flask, to which 1 mgof compound 223A in 0.2 mL ethanol was added. The flask was incubated at28° C. and 250 rpm for 24 hours, and the reaction culture was extractedwith EtOAc (10 mL). The EtOAc extract was dried under N₂ and the residuewas dissolved in 1 mL of MeOH (reaction extract).2. Product AnalysisHPLC:10 μL of the reaction extract was injected into HPLC column (YMC ODS-AQC-18 column, 150×6.0 mm i.d.). The column was eluted with 1 mM HCl inwater/CH₃CN at 1.2 mL/min flow rate: 30 to 60% CH₃CN over 8 min, 60 to85% CH₃CN over 0.5 min, 85% CH₃CN for 1 min, 85 to 30% CH₃CN over 0.5min. The eluents were monitored at 300 nm. Two major peaks with about a1 to 1 area ratio were observed, which had the same UV spectra as thoseof compounds 459 and 331, and had retention times of 4.55 min and 7.23min, respectively, matching the retention times of authentic samples ofcompound 459 (4.53 min) and compound 331 (7.2 min).LC/MSThe reaction extract: two major UV peaks.Peak 1, Tr 4.68 min: 391 [M+H]⁺, 343, 319, 303, 289Peak 2, Tr 5.35 min: 375 [M+H]⁺, 345

Authentic samples

Compound 459, Tr 4.82 min: 391 [M+H]⁺, 343, 319, 289

Compound 331, Tr 5.48 min: 375 [M+H]⁺, 345

Microbial Hydroxylation of Compound 331

To a 500 mL flask containing 100 mL of the transformation medium wasadded one frozen vial (approximately 2 mL) of Streptomyces griseus ATCC10137. The transformation medium was prepared as follows: to a 2 Lplastic beaker was added 20 g of dextrose, 5.0 g of yeast extract, 5.0 gof soybean meal, 5.0 g of sodium chloride, 5.0 g of potassium phosphate(dibasic) and one L of deionized water, and the mixture was stirred atroom temperature for 3 to 30 min. The pH of the mixture was thenadjusted to 7.0 with 1 N HCl or 1 N NaOH. The resulting mixture wasdispensed into 500 mL flasks (100 mL per flask). The flasks were coveredwith Bio/Wrap and autoclaved at 121° C. for 15 min. and cooled down toroom temperature before use.The culture was incubated at 28° C. and 250 rpm for 3 days. One mL ofthe resulting culture was added to a 500 mL flask containing 100 mL ofthe transformation medium and the flask was incubated at 28° C. and 250rpm for 24 hours. Ten mL of the resulting culture was transferred to a50 mL flask, to which 1 mg of compound 331 in 0.2 mL ethanol was added.The flask was incubated at 28° C. and 250 rpm for 23 hours. HPLCanalysis showed that the peak area ratio of compound 459 to compound 331in the reaction culture was about 1.1/1.

EXAMPLE 460(1aα,2β,2aα,5aα,6βb,6aα)-4-[2-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-6-methyl-3,5-dioxo-2,6-epoxy-4H-oxireno[f]isoindol-4-yl]-1-naphthalenecarbonitrile(460)

Compound 231A (2.00 g, 4.10 mmol) was dissolved in dicholomethane (40mL) and cooled to 0° C. mCPBA (2.36 g, 8.20 mmol) was added. Thereaction mixture was then warmed up to room temperature and stirredunder argon for 18 hours, followed by the addition of 10% Na₂SO₃ (25 mL)and saturated NaHCO₃ (25 mL). After stirring for 20 minutes, the organiclayer was separated and the aqueous layer was extracted withdicholomethane (3×50 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure to give2.0 g compound 460 as light yellow solid. HPLC: 99% at 4.00 min(retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm eluting with10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm). MS (ES): m/z [M+H]=505.19

EXAMPLE 461[3aR-(3aα,4β,7β,7aα)]-4-[4-Ethyloctahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile&[3aS-(3aα,4β,7β,7aα)]-4-[4-Ethyloctahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(461i & 461ii)

The racemic mixture of compounds 245C was separated by normal phasepreparative chiral HPLC using a Chiracel AD column (5 cm×50 cm), elutingwith 20% solvent B (50% MeOH/EtOH) in solvent A (Heptane), flow rate: 50mL/min. Compound 461i eluted from 80 min to 100 min and compound 461iieluted from 125 min to 150 min.

The absolute conformation for compounds 461i and 461ii was notdetermined. For simplicity in nomenclature, compound 461i is designatedherein as having an “R” configuration and compound 461ii as having an“S” configuration. Enantiomerically pure products derived from compound461i are designated herein as having an “R” configuration andenantiomerically pure products derived from compound 461ii aredesignated herein as having an “S” configuration.

EXAMPLE 462[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyanophenoxy)ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(462)

DBAD (29.5 mg, 0.128 mmol) was added to a solution of PPh₃ (33.6 mg,0.128 mmol) in THF (0.5 mL). After stirring for 10 min, 4-cyanophenol(15.2 mg, 0.128 mmol) was added and the reaction mixture was stirred foran additional 5 min. Compound 461i (18.3 mg, 0.047 mmol) was added andthe mixture was stirred at rt for 2 h. The reaction was concentratedunder reduced pressure. Purification by flash chromatography on silicagel eluting with 40% EtOAc/hexane gave 16.9 mg (0.034 mmol, 73.2%) ofcompound 462. HPLC conditions: 98% at 3.64 min (retention time) (YMC S5ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2%H₃PO₄, detecting at 220 nm). MS (ES): m/z 492.23 [M+H]⁺.

EXAMPLE 463[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyanophenoxy)ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(463)

DBAD (29.5 mg, 0.128 mmol) was added to a solution of PPh₃ (33.6 mg,0.128 mmol) in THF (0.5 mL). After stirring for 10 min, 4-cyanophenol(15.2 mg, 0.128 mmol) was added and the reaction mixture was stirred foran additional 5 min. Compound 461ii (18.3 mg, 0.047 mmol) was added andthe mixture was stirred at rt for 2 h. The reaction was concentratedunder reduced pressure. Purification by flash chromatography on silicagel eluting with 40% EtOAc/hexane gave 18.1 mg (0.037 mmol, 78.4%) ofcompound 463. HPLC conditions: 97% at 3.63 min (retention time) (YMC S5ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2%H₈PO₄, detecting at 220 nm). MS (ES): m/z 492.17 [M+H]⁺.

EXAMPLE 464(1aα,2β,2aα,5aα,6β,6aα)-5-[2-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-6-methyl-3,5-dioxo-2,6-epoxy-4H-oxireno[f]isoindol-4-yl]-8-quinolinecarbonitrile(464H)

A. 8-Bromo-5-nitro-quinoline (464A)

8-Bromoquinoline (25.00 g, 120.2 mmol) was dissolved in sulfuric acid(82.5 mL) at rt and then cooled to 0° C. HNO₃ (fuming, 32.5 mL) was thenslowly added over a 10 minute period. The reaction was then warmed to rtand then to 65° C. After 48 h at 65° C., the reaction was cooled to rtand poured onto 500 g of ice. This solution was extracted with methylenechloride (5×200 mL). The organic layers were washed once with brine anddried over anhydrous sodium sulfate. Concentration gave the crudecompound 464A as a light yellow solid (28.6 g, 94%). HPLC: 98% at 2.717min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm).

B. 5-Nitro-quinoline-8-carbonitrile (464B)

Compound 464A (15.0 g, 59.3 mmol) was dissolved in DMF (120 mL) and zinccyanide (4.20 g, 35.9 mmol) was added. Bis(diphenylphosphino)ferrocene(3.00 g, 5.40 mmol) and tris(benzylidineacetone)dipalladium (3.00 g,3.30 mmol) were then added and the reaction was heated to 100° C. for1.5 h. The reaction was cooled to 22° C. and then poured intoconcentrated ammonium hydroxide (900 mL) resulting in an orangeprecipitate which was filtered and rinsed with cold water (1 L). Theresulting precipitate was dissolved in methylene chloride, washed withbrine (1×300 mL) and then dried over anhydrous sodium sulfate.Concentration in vacuo gave the crude material as an orange solid whichwas purified by flash chromatography on silica gel eluting withmethylene chloride to give 6.01 g (51%) of compound 464B as a yellowsolid. HPLC: 99% at 1.900 min (retention time) (YMC S5 ODS column,4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

C. 5-Amino-quinoline-8-carbonitrile (464C)

Compound 464B (6.00 g, 30.1 mmol) was dissolved in THF (150 mL) atreflux with mechanical stirring. EtOH (150 mL) was then added followedby aqueous ammonium chloride (2.4 g/225 mL water). The mixture washeated at 70° C. and then iron powder (325 mesh, 6.75 g, 120 mmol) wasadded with vigorous mechanical stirring. After 1 h, the reaction wascooled to 22° C. and filtered through Celite rinsing with methylenechloride. The filtrate was then concentrated to ˜250 mL and the pH wasadjusted to 10 by addition of 1N NaOH. The solution was then extractedwith ethyl acetate (5×150 mL). The combined organic layers were washedonce with brine (250 mL) and then dried over anhydrous magnesiumsulfate. Concentration in vacuo gave 5.09 g (100%) of compound 464C as ayellow solid. HPLC: 99% at 1.143 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 170.16 [M+H]⁺.

D. 5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-quinoline-8-carbonitrile (464D)

Compound 464C (7.00 g, 41.4 mmol) and maleic anhydride (6.00 g, 62.1mmol) were combined in a sealed tube and THF (10 mL) was added. Thereaction mixture was heated to 115° C. for 15 min then cooled to roomtemperature, resulting in the precipitation of the intermediate acidamide. The solid was filtered and rinsed with cold THF to give 11.0 g ofthe acid as a yellow solid. To the above acid amide was added Ac₂O (25mL) in a sealed tube and the mixture was heated at 100° C. for 15 minthen cooled to room temperature. The resulting solid was filtered andrinsed with cold diethyl ether to give 8.30 g (80%) of compound 464D asa yellow solid. HPLC: 97% at 1.783 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

E.(3aα,4β,7β,7aα)-5-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-1,3,3a,4,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(464E)

Compound 464D (6.00 g, 24.1 mmol) was dissolved in a mixture of benzene(80 mL) and acetone (20 mL) followed by addition of compound 204A (14.46g, 60.15 mmol). The mixture was heated at 80° C. for 14 h and thencooled to 22° C. Concentration in vacuo at 40° C. followed by additionof acetone (40 mL) and concentration again at 40° C. The resultingyellow oil was purified by flash column chromatography on silica geleluting with 0-10% acetone in chloroform to give 9.98 g (85%) ofcompound 464E as a yellow oil. Compound 464E was shown to be a singleisomer by NMR spectroscopy. HPLC: 97% at 3.853 min (retention time) (YMCS5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 490.35 [M+H]⁺.

F.(1aα,2β,2aα,5aα,6β,6aα)-5-[2-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-6-methyl-3,5-dioxo-2,6-epoxy-4H-oxireno[f]isoindol-4-yl]-8-quinolinecarbonitrile (464F)

To a solution of compound 464E (0.050 g, 0.10 mmol) in dichloromethane(2 mL) was added mCPBA (60% mixture, 0.063 g, 0.22 mmol). The reactionmixture was stirred at room temperature for 16 h and then additionaldichloromethane (20 mL), saturated NaHCO₃ (10 mL) and 10% Na₂SO₃ (10 mL)were added. The mixture was stirred vigorously for 40 min, the organiclayer was then separated, washed once with brine, and dried over Na₂SO₄.Concentration in vacuo gave 48 mg (96%) of compound 464F as a lightyellow solid. HPLC: 98% at 3.783 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 506.25 [M+H]⁺.

G.(1aα,2β,2aα,5aα,6β,6aα)-5-[Octahydro-2-(2-hydroxyethyl)-6-methyl-3,5-dioxo-2,6-epoxy-4H-oxireno[f]isoindol-4-yl]-8-quinolinecarbonitrile(464G)

Compound 464F (1.30 g, 2.57 mmol) was dissolved in 2% conc. HCl/EtOH (50mL). The reaction mixture was stirred at room temperature for 1 h andthen saturated NaHCO₃ (50 mL) and dichloromethane (100 mL) were added.The organic layer was separated, washed once with brine and dried overNa₂SO₄. Concentration in vacuo gave 930 mg (93%) of compound 464G as ayellow solid. HPLC: 98% at 1.863 (retention time) (YMC S5 ODS column,4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z392.20 [M+H]⁺.

H.(1aα,2β,2aα,5aα,6β,6aα)-5-[2-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-6-methyl-3,5-dioxo-2,6-dioxo-2,6-epoxy-4H-oxireno[f]isoindol-4-yl]-8-quinolinecarbonitrile(464H)

Triphenylphosphine (25 mg, 0.096 mmol) and DBAD (22 mg, 0.096 mmol) weremixed in THF (0.5 mL) under argon. After 5 min, 5-chloro-2-pyridinol (13mg, 0.096 mmol) was added. The reaction mixture was stirred at 22° C.for another 10 min, then compound 464G (25 mg, 0.064 mmol) was added.The reaction mixture was stirred at 22° C. under argon for 3 h, and thenconcentrated in vacuo. The crude material was purified by preparativeTLC on silica gel eluting with 10% acetone in chloroform to give 11 mg(23%) of compound 464H as a white solid. HPLC: 100% at 3.177 (retentiontime) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoringat 220 nm). MS (ES): m/z 503.14 [M+H]⁺.

EXAMPLE 465(3aα,4β,7β,7aα)-5-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(465)

Compound 464E (2.40 g, 4.91 mmol) was dissolved in ethyl acetate andPd/C (10% Pd, 0.50 g) was added. Hydrogen was then introduced via aballoon. After 3 h, the reaction was purged with nitrogen and filteredthrough Celite, rinsing with ethyl acetate. Concentration in vacuo gave2.39 g (99%) of compound 465 as a yellow oil. HPLC: 95% at 4.013 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 492.22 [M+H]⁺.

EXAMPLE 466(3aα,4β,7β,7aα)-5-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(466)

Compound 465 (1.40 g, 2.85 mmol) was dissolved in 2% conc. HCl/MeOH (20mL) and stirred at 22° C. for 3 h. The reaction was then concentrated to˜5 mL volume and quenched with a minimum amount of sat. aq. sodiumbicarbonate. This solution was then extracted with methylene chloride(3×30 mL) and the combined organic layers were dried over anhydroussodium sulfate. Concentration in vacuo gave 0.893 g (93%) of compound466 as a yellow solid. This material was taken on without furtherpurification. HPLC: 98% at 2.140 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 378.25 [M+H]⁺.

EXAMPLE 467[3aR-(3aα,4β,7β,7aα)]-5-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(467Bi) &[3aS-(3aα,4β,7β,7aα)]-5-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(467Bii)

A.[3aR-(3aα,4β,7β,7aα)]-5-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(467Ai) &[3aS-(3aα,4β,7β,7aα)]-5-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(467Aii)

Compounds 465 was separated into its individual antipodes by normalphase preparative chiral HPLC. A Chiralcel OD column (50×500 mm) wasused with a flow rate of 50 mL/min (16% EtOH/hexanes) monitoring at 220nm. The faster eluting antipode compound 467Ai had a retention time of40.85 min (>99% ee) and the slower antipode compound 467Aii had aretention time of 62.81 min (>99% ee). Both antipodes were isolated aswhite solids after separation. The absolute conformation for compounds467Ai & 467Aii was not established. For simplicity in nomenclature,compound 467Ai is designated herein as having an “R” configuration andcompound 467Aii as having an “S” configuration. Enantiomerically pureproducts derived from compound 467Ai are designated herein as having a“R” configuration and enantiomerically pure products derived fromcompound 467Aii are designated herein as having an “S” configuration.

B.[3aR-(3aα,4β,7β,7aα)]-5-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(467Bi) &[3aS-(3aα,4β,7β,7aα)]-5-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(467Bii)

Both antipodes were deprotected as described in example 464G to give thecorresponding alcohols, compounds 467Bi and 467Bii as white solids:

Compound 467Bi: HPLC: 98% at 2.110 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 378.21 [M+H]⁺.

Compound 467Bii: HPLC: 98% at 2.117 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 378.20 [M+H]⁺.

EXAMPLE 468(3aα,4β,7β,7aα)-8-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-5-quinoxalinecarbonitrile(468C)

A. 8-Nitro-quinoxaline-5-carbonitrile (468A)

2,3-Diamino-4-nitro-benzonitrile (0.050 g, 0.28 mmol, as prepared inWO-98/32439) was added to solution of glyoxal (40% in water, 0.032 mL,0.28 mmol) in acetic acid (0.75 mL) and stirred at 22° C. for 3 h. Thereaction was cooled to 0° C. and water (2.0 mL) was added and the pH wasadjusted to 9.0 by addition of ammonium hydroxide which caused theproduct to precipitate. The mixture was then filtered and rinsed withcold water. Drying in vacuo gave 0.039 g (70%) of compound 468A as anorange solid. HPLC: 100% at 2.037 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

B. 8-Amino-quinoxaline-5-carbonitrile (468B)

Compound 468A (0.200 g, 1.00 mmol) was suspended in acetic acid (5.0 mL)and iron powder (325 mesh, 0.112 g, 2.00 mmol) was added. The reactionwas then heated at 70° C. for 20 min and then cooled to 22° C. Thereaction was filtered through Celite, rinsing with ethyl acetate. Theethyl acetate rinse was collected and washed with sat. aq. K₂CO₃. Theaqueous layer was extracted with ethyl acetate (3×20 mL) and thecombined organic layers were dried over anhydrous magnesium sulfate.Concentration in vacuo gave 0.170 g (100%) of compound 468B as a yellowsolid. HPLC: 88% at 1.677 min (retention time) (YMC S5 ODS column,4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z171.29 [M+H]⁺.

C.(3aα,4β,7β,7aα)-8-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-5-quinoxalinecarbonitrile(468C)

Compound 468B (0.060 g, 0.35 mmol) was suspended in toluene (1.0 mL)with magnesium sulfate (0.060 g) and compound 20A (0.104 g, 0.529 mmol).TEA (0.2 mL) was then added and the mixture was heated to 145° C. in asealed tube. After 16 h the reaction was cooled to 22° C. and filteredthrough Celite, rinsing with acetone. The mixture was concentrated invacuo and then purified by preparative TLC on silica gel eluting with 7%ethyl acetate/methylene chloride. This gave 0.018 g (15%) of compound468C as a yellow solid. HPLC: 100% at 2.040 and 2.133 min (atropisomers,retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 349.33 [M+H]⁺.

EXAMPLE 469(3aαc,4β,7β,7aα)-1,2,3,4-Tetrahydro-8-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-5-quinoxalinecarbonitrile(469B)

A. 8-Amino-1,2,3,4-tetrahydro-quinoxaline-5-carbonitrile (469A)

Compound 468A (0.037 g, 0.18 mmol) was dissolved in a mixture of ethylacetate (1.0 mL)/ethanol (1.0 mL) and 10% Pd/C (0.050 g) was added.Hydrogen was then introduced via a balloon. After 2 h, the reaction waspurged with nitrogen and filtered through Celite, rinsing with ethylacetate. Concentration in vacuo gave 0.029 g (90%) of compound 469A as ared oil, which was taken on without further purification. HPLC: 97% at3.217 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

B.(3aα,4β,7β,7aα)-1,2,3,4-Tetrahydro-8-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-5-quinoxalinecarbonitrile(469B)

Compound 469A (0.029 g, 0.17 mmol) was suspended in toluene (1.0 mL)with magnesium sulfate (0.030 g) and compound 20A (0.050 g, 0.256 mmol).TEA (0.2 mL) was then added and the mixture was heated at 145° C. in asealed tube. After 48 h the reaction was cooled to 22° C. and filteredthrough Celite, rinsing with acetone. The mixture was concentrated invacuo and then purified by preparative TLC eluting with 20% acetone inchloroform. This gave 0.014 g (24%) of compound 469B as a yellow solid.HPLC: 85% at 2.267 min (retention time) (YMC S5 ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 353.19[M+H]⁺.

EXAMPLE 470(3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-1-isoquinolinecarbonitrile(470E)

A. 4-Bromo-isoquinoline 2-oxide (470A)

A solution of 4-bromoisoquinoline (4.16 g, 18.6 mmol) in 100 mL ofchloroform was added dropwise over 1 h to a solution of 70% mCPBA (12.4g, 50.3 mmol) in 100 mL of chloroform at room temperature. Afterstirring 18 h, the reaction mixture was washed with 1N NaOH (2×150 mL),dried over magnesium sulfate and concentrated in vacuo to afford 4.23 g(94%) of compound 470A as an off-white solid. ¹H NMR-400 MHz (CDCl₃): δ8.71 (s, 1H), 8.43 (s, 1H), 8.09 (d, 1H, J=8 Hz), 7.70 (m, 3H).

B. 4-Bromo-isoquinoline-1-carbonitrile (470B)

1,8-Diazabicyclo[5.4.0]undec-7-ene (1.67 mL, 11.2 mmol) was added to amixture of compound 470A (1.12 g, 5.00 mmol) and cyanotrimethylsilane(0.75 mL, 5.5 mmol) in 35 mL of THF. The resulting homogeneous mixturewas refluxed for 20 min. After concentrating in vacuo, the residue waspurified by flash chromatography on a 5×15 cm silica gel column, elutingwith 3:1 hexane:ethyl acetate to give 0.95 g (82%) of compound 470B as awhite powder. ¹H NMR (400 MHz, CDCl₃): δ 8.85 (s, 1H), 8.36 (d, 1H,J=8.5 Hz), 8.28 (d, 1H, J=8.5 Hz), 7.96 (t, 1H, J=8.5 Hz), 7.89 (t, 1H,J=8.5 Hz).

C. 4-(2,4-Dimethoxy-benzylamino)-isoquinoline-1-carbonitrile (470C)

A mixture of compound 470B (699 mg, 3.00 mmol) and2,4-dimethoxybenzylamine (4.8 mL, 30 mmol) in 15 mL of acetonitrile wasrefluxed for 16 h. After concentration in vacuo, the residue waspurified on a 5×15 cm silica gel column, eluting with 3:2 hexane:ethylacetate to afford 290 mg (30%) of 470C as a light yellow solid. HPLC:1.76 min (retention time) (Phenomenex C-18, 5 micron column, 4.6×30 mm,eluting with 10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4mL/min, monitoring at 254 nm).

D. 4-Amino-isoquinoline-1-carbonitrile (470D)

Compound 470C (50 mg, 0.16 mmol) was treated with trifluoroacetic acid(0.5 mL) for 1 h. The highly colored mixture was partitioned betweenethyl acetate (30 mL) and 1N NaOH (30 mL). After washing with brine (15mL), the organic layer was dried over magnesium sulfate and concentratedin vacuo to afford 24 mg (92%) of compound 470D as a yellow solid. HPLC:99% at 1.09 min (retention time) (Phenomenex C-18, 5 micron column,4.6×30 mm, eluting with 10-90% aqueous methanol over 2 mincontaining0.1% TFA, 4 mL/min, monitoring at 254 nm). MS (ES⁺): m/z 170.2 [M+H]⁺.

An alternative route to the synthesis of compound 470D is as follows. Amixture of compound 470B (1.17 g, 5.02 mmol), benzophenone imine (1.05mL, 6.26 mmol), palladium acetate (25 mg, 0.11 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′ binaphthyl (100 mg, 0.161 mmol) andcesium carbonate (2.30 g, 7.06 mmol) in 20 mL of toluene was heated at100° C. for 20 h. The reaction mixture was diluted with ethyl ether (200mL) and filtered through Celite. After concentrating the filtrate, theresidue was dissolved in 120 mL of THF and treated with 40 mL of 1N HCl.After standing for 2 h at room temperature, the mixture was partitionedbetween ethyl acetate (150 mL) and 0.25 N NaOH (160 mL). After washingwith brine (100 mL), the organic layer was dried over magnesium sulfate.The organic layer was filtered and ˜50 g of celite was added to thefiltrate. After concentration in vacuo, the powdery residue was purifiedby flash chromatography on a 5×15 cm silica gel column eluting with 1 Leach of 1:1 ethyl acetate:hexane, 6:4 ethyl acetate:hexane and 8:2 ethylacetate:hexane to give 450 mg (53%) of 470D as a yellow powder.

E.(3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-1-isoquinolinecarbonitrile(470E)

A mixture of compound 470D (24 mg, 0.14 mmol), compound 20A (55 mg, 0.28mmol), triethylamine (0.1 mL), magnesium sulfate (100 mg),2-methoxyethylether (0.5 mL) and DMF (0.1 mL) was heated in a sealedvessel to 250° C. for a total of 2.5 h using a microwave heating device.After partitioning the reaction mixture between ethyl acetate (25 mL)and water (25 mL), the organic layer was dried over magnesium sulfateand concentrated in vacuo. Approximately half of the residue waspurified by reverse phase preparative HPLC (YMC S5 ODS 20×50 mm, elutingwith 10-100% aqueous methanol over 10 mincontaining 0.1% TFA, 20mL/min). Concentration of the pure fraction afforded 6 mg (12%) ofcompound 470E as a white powder. HPLC: 99% at 1.42 min (retention time)(Phenomenex C-18, 5 micron column, 4.6×30 mm, eluting with 10-90%aqueous methanol over 2 min containing 0.1% TFA, 4 mL/min, monitoring at254 nm). MS (ES⁺): m/z 348.23 [M]⁺.

EXAMPLE 471[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(471Di) &[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(471Dii)

A. 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(471A)

A mixture of 3-trifluoromethyl-4-cyano-aniline (24.0 g, 129 mmol) andmaleic anhydride (14.0 g, 143 mmol) in 50 mL of acetic acid was heatedat 115° C. overnight. A precipitate was obtained during the heatingperiod. The reaction was allowed to stand at rt for an additionalovernight period. The solid was removed by filtration, the filter cakewas washed with diethyl ether and dried to give 21 g (79 mmol, 61%) ofcompound 471A as an off white solid. HPLC: 100% at 2.11 min (retentiontime) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoringat 220 nm).

B.(3aα,4β,7β,7aα)-4-(1,3,3a,4,7,7a-Hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(471B)

A suspension of compound 471A (13.0 g, 48.8 mmol) and 2,5-dimethylfuran(10.5 mL, 98.6 mmol) in 50 mL of toluene was heated at 60° C., underargon. A solution was obtained on initial heating and a precipitate wasobserved after approximately 1 h. Heating was continued overnight. Aftercooling to rt, the suspension was allowed to stand at 4° C. overnight.The resulting solid was filtered and the filter cake was washed withcold toluene followed by air drying to give 13.2 g of pure compound 471Bas a white solid. The filtrate volume was reduced in vacuo by one halfand the resulting solution was treated as above to yield an additional2.8 g of pure compound 471B (total 16.0 g, 90%). HPLC: 90% at 3.65 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm).

C.(3aα,4β,5β,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(471C)

A solution of compound 471B (25 g, 69 mmol) in 125 mL of THF, in a dryflask under nitrogen, was cooled to 10° C. with an ice bath. To thissolution was added neat borane-dimethylsulfide complex (13.0 mL, 138mmol) dropwise over 10 min, while maintaining a reaction temperature of<15° C. The reaction mixture was stirred for 30 min at rt and then in anice bath cooled to 101C. To the cool solution was slowly added 480 mL ofpH 7 phosphate buffer, which resulted in a strong exothermic reactionand vigorous gas evolution. The solution was maintained at <21° C.throughout the addition by means of an ice bath. To the resultingsolution was added 240 mL of ethanol and the resulting mixture wascooled to 5° C. with an ice bath. To the cooled solution was added 50 mLof 30% hydrogen peroxide and the resulting mixture was stirred at 10-20°C. for 1.5 h. The mixture was extracted with ethyl acetate (2×1 L) andthe combined organic layers were washed with 10% sodium sulfite (1×500mL) and brine (2×300 mL) and dried over MgSO₄. Concentration in vacuoafforded 29 g of crude product as a white solid. This material wassubjected to flash chromatography on a 1.2 L column of silica gelequilibrated with 100% CH₂Cl₂. The material was applied to the column asa solution consisting of 100 mL EtOAc (warn) and 400 mL CH₂Cl₂. Initialelution with CH₂Cl₂ (3 L), followed by 25% EtOAc/75% CH₂Cl₂ (3 L) andfinally 50% EtOAc/50% CH₂Cl₂ (6 L) gave 11.8 g (45%) of compound 471Cwhich is a racemic mixture.

Alternatively compound 471C can be made by the following approach: A dryflask containing compound 471B (8.90 g, 24.6 mmol) and Wilkinson'scatalyst (0.57 mg, 0.62 mmol) was degassed 4× with vacuum/argon. THF (40mL) was added to the flask and the mixture was stirred until a clearbrown solution was obtained. Catecholborane (49 mL, 49 mmol, 1 M in THF)was then added dropwise over 20 min and a slight exotherm was observed.Stirring was continued for 45 min followed by cooling of the reactionmixture with an ice bath. pH 7 phosphate buffer (175 mL) was slowlyadded, followed by the consecutive addition of ethanol (87 mL) and 30%hydrogen peroxide (18 mL). Stirring was continued with cooling and thereaction progress was monitored by HPLC for 4 h. The reaction wasextracted with CH₂Cl₂ (3×250 mL). The combined extracts were washed with1:1 1N NaOH:15% sodium sulfite (300 mL) and brine, dried over MgSO₄, andthe solvent was removed in vacuo to afford 8.5 g of a tan solid. Thecrude product was subjected to flash chromatography on a 500 cm³ silicagel column eluting with a gradient of 25-50% EtOAc/CH₂Cl₂ to give 6.00 gcompound 471C (15.8 mmol, 64%) as a white solid. HPLC: 90% at 2.45 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 381.11 [M+H]⁺.

D.[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(471Di) &[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(471Dii)

The individual antipodes of compound 471C were separated by normal phasepreparative chiral HPLC (CHIRALPAK AD, 5×50 cm column). A 2.5 g portionof 471C was dissolved into 25 mL of warm acetone and diluted to 50-75 mLwith hexane for injection. Isocratic elution with 20% MeOH/EtOH (1:1) inheptane at 50 mL/min gave the faster eluting compound 471Di (ChiralHPLC: 10.02 min; CHIRALPAK AD 4.6×250 mm column; isocratic elution with20% MeOH/EtOH (1:1) in heptane at 1 mL/min) and the slower elutingcompound 471Dii (Chiral HPLC: 14.74 min; CHIRALPAK AD 4.6×250 mm column;isocratic elution with 20% MeOH/EtOH (1:1) in heptane at 1 mL/min).Compounds 471Di & 471Dii: HPLC: 90% at 2.45 min (retention time) (YMC S5ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 381.11 [M+H]⁺. The absolute stereochemistry of compounds 471Di& 471Dii was determined by single crystal X-ray diffraction studies andis as described by the designated nomenclature.

The resulting HPLC purified fractions of compounds 471Di & 471Dii werefurther purified by crystallization using any one of the proceduresdescribed below.

1) From Ethyl Acetate

-   -   A 700 mg portion of compound 471Di, obtained after chiral        chromatography as described above, was dissolved in ethyl        acetate (10 mL) at rt. The solution was diluted with small        portions of hexane (20 mL) until cloudiness was observed. The        solution was allowed to stand overnight at rt. The resulting        white solid was filtered and air dried to afford 430 mg of        compound 471Di as a white powder. This sample was further dried        at 60° C. (3 h, 0.5 Torr), then at 70° C., (12 h, 0.5 Torr).        2) From Acetone    -   A 500 mg portion of compound 471Di, obtained after chiral        chromatography as described above, was dissolved in a minimal        amount of acetone (3 mL) and slowly diluted with hexane (1 mL).        The clear colorless solution was allowed to stand overnight at        rt. The resulting white solid was filtered and air dried to        afford 440 mg of compound 471Di as a white powder. This sample        was further dried at 60° C., (3 h, 0.5 Torr) then at 70° C., (12        h, 0.5 Torr).        3) From Methanol    -   A 500 mg portion of compound 471Di, obtained after chiral        chromatography as described above, was dissolved in 5 mL of hot        (steam bath) methanol. The clear colorless solution was allowed        to stand at rt for 2 h, then at 4° C. overnight. The resulting        solid was filtered, washed with minimal cold methanol and air        dried for to afford 360 mg of compound 471Di as a white powder.        This sample was further dried at 70° C., (12 h, 0.5 Torr).        4) From CH₂Cl₂    -   A 7.00 g portion of compound 471Di, obtained after chiral        chromatography as described above, was dissolved in 75 mL of        CH₂Cl₂ at rt. The clear and colorless solution was slowly        diluted with hexane (48 mL) until crystallization was observed.        The solution was allowed to stand at rt for 1 h, then at 4° C.        overnight. The resulting crystalline material was filtered and        then washed with a minimal amount of cold 2:1 CH₂Cl₂:hexane. The        large crystals were ground to a fine powder and dried at 50° C.        (12 h, 0.5 Torr) to yield 5.96 g of compound 471Di as a white        powder

EXAMPLE 472(3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(472)

A solution of compound 471B (500 mg, 1.38 mmol) in ethyl acetate (10mL), containing 10% Pd/C (25 mg, cat.) was stirred at rt under anatmosphere of hydrogen introduced via a balloon. After 2 h the reactionwas filtered through Celite and the filter cake was washed with EtOAc.The clear, colorless filtrate was concentrated in vacuo to yield 501 mg(1.38 mmol, 100%) of compound 472 as a white solid. No furtherpurification was required. HPLC: 99% at 3.04 min (retention time) (YMCS5 ODS column, 4.6×50 mm, 10-90% aqueous methanol over 4 mincontaining0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ESI): m/z382.2 [M+NH₄]⁺.

EXAMPLE 473(3aα,4β,5β,7β,7aα)-4-[5-(Acetyloxy)octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(473)

To a solution of compound 471C (1.50 g, 3.95 mmol) in 10 mL of pyridine,cooled to 0° C. under argon, was added acetic anhydride (0.42 mL, 4.4mmol) dropwise, followed by DMAP (5 mg, 0.04 mmol). Stirring wascontinued at rt for 4 h. The solution was concentrated in vacuo and theresulting residue was diluted with ethyl acetate, and washedconsecutively with 1N HCl (2×), brine (2×), sat. NaHCO₃, and brine (2×).The organic layer was dried over MgSO₄ and concentrated in vacuo. Theresulting solid was dried at 60° C. (20 h, 0.5 Torr) to yield 1.55 g(3.67 mmol, 93%) of compound 473 as a white crystalline solid. HPLC: 99%at 2.10 min (retention time) (Phenomenex Luna C18 column, 2×30 mm,0-100% aqueous acetonitrile over 3 mincontaining 10 mM NH₄OAc at 1mL/min, monitoring at 220 nm). MS (ESI): m/z 421.4 [M−H]⁻.

EXAMPLE 474(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(2-methyl-4-benzoxazolyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(474F)

A. 2-Methyl-4-nitrobenzoxazole (474A)

To 2-amino-3-nitrophenol (6.17 g, 40.0 mmol) was addedtriethylorthoacetate (25.96 g, 160.0 mmol) and the mixture was heated at100° C. for 12 h to give a dark red solution. Cooling to roomtemperature produced a crystalline mass which was filtered and washedwith hexane to give compound 474A (6.78 g, 95%) as light maroon needles.HPLC: 98.1% at 1.86 min (retention time) (YMC S5 ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 μm). MS (ES): m/z 179.08[M+H]⁺.

B. 4-Amino-2-methylbenzoxazole (474B)

Compound 474A (6.78 g, 38.1 mmol) was dissolved in a 1:1 mixture of 10%acetic acid/ethyl acetate (100 mL total volume) and heated to 65° C.Iron powder (10.63 g, 190.2 mmol) was added portionwise. After stirringfor 3 h, TLC indicated complete consumption of starting material. Thecooled reaction mixture was filtered through a pad of Celite and the padwas washed with 50 mL of ethyl acetate. The organic layer was separated,washed with water (2×25 mL), brine (1×25 mL), dried over MgSO₄, filteredand concentrated in vacuo. The crude material was purified by flashchromatography on silica gel eluting with 25% ether/CH₂Cl₂ to give 3.90g (69%) of compound 474B as a light brown solid. HPLC: 95.8% at 2.43 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 149.11 [M+H]⁺.

C. 4-Amino-7-bromo-2-methylbenzoxazole (474C)

Compound 474B (3.90 g, 26.3 mmol) was dissolved in DMF (45 mL) andcooled to −5° C. and N-bromosuccinimide (4.68 g, 26.3 mmol) was added insmall portions and the reaction stirred for 5 h. The mixture was pouredinto 150 mL of ice water to give a cream colored solid which wasfiltered, washed with water, dissolved in CH₂Cl₂, dried over MgSO₄,filtered and concentrated in vacuo. Purification of the crude materialby flash chromatography on silica gel eluting with 20% ether/CH₂Cl₂ gavecompound 474C (3.36 g, 56%) as a beige solid. HPLC: 95.4% at 2.583 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 228.03 [M+H]⁺.

D. 1-(7-Bromo-2-methyl-benzoxazol-4-yl)-pyrrole-2,5-dione (474D)

Compound 474C (1.40 g, 6.17 mmol) was dissolved in 20 mL of acetic acid,maleic anhydride (0.635 g, 6.47 mmol) was added and the reaction washeated at reflux under nitrogen for 5 h. The solvent was removed invacuo and the crude product was purified by flash chromatography onsilica gel eluting with 10% ether/CH₂Cl₂ to give compound 474D (1.73 g,91%) as a pale yellow solid. HPLC: 93.6% at 1.36 min. (Phenomenexcolumn, 30×4.6 mm, 10-90% aqueous methanol over 2 mincontaining 0.1%TFA, 5 mL/min, monitoring at 220 nm. MS (ES): m/z 308.02 [M+H]⁺.

E.(3aα,4β,7β,7aα)-2-(7-Bromo-2-methyl-4-benzoxazolyl)-3a,4,7,7a-tetrahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(474E)

Compound 474D (0.307 g, 1.00 mmol) was dissolved in benzene (2 mL) and2,5-dimethylfuran (0.154 g, 1.60 mmol) was added via syringe. Thereaction mixture was heated to 60° C. for 12 h. The cooled reactionmixture was concentrated in vacuo at 40° C. to give compound 474E as anoff-white foam which was used directly in the next reaction withoutpurification.

F.(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(2-methyl-4-benzoxazolyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(474F)

Compound 474E (0.403 g, 1.00 mmol) was dissolved in EtOH/EtOAc (4 mL/4mL) and 10% Pd/C (100 mg) was added. The reaction mixture was stirred atroom temperature for 6 h under an atmosphere of H₂ supplied by a balloonand then filtered through Celite. Concentration of the filtrate in vacuogave a brown solid. Purification by flash chromatography on silica geleluting with 10% acetone/CHCl₃ (250 mL), 15% acetone/CHCl₃ (250 mL), and20% acetone/CHCl₃ (250 mL) gave compound 474F (0.089 g, 27%) as a whitefoam. HPLC: 91% at 2.28 min (retention time) (YMC S5 ODS column, 4.6×50mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 328.34[M+H]⁺.

EXAMPLE 475(3aα,4β,7β,7aα)-2-(7-Bromo-2-methyl-4-benzoxazolyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(475)

Compound 474E (0.202 g, 0.501 mmol) was dissolved in 1/1 EtOAc/EtOH (10mL) and 10% Pt/C (100 mg) was added. The reaction mixture was stirred atroom temperature under an H₂ balloon for 6 h. The reaction was filteredthrough Celite and concentrated in vacuo. Purification by flashchromatography on silica gel eluting with 10% ether/CH₂Cl₂ gave 0.063 g(31%) of compound 475 as a colorless oil which solidified upon standingto give a white solid. HPLC: 92.5% at 2.83 min (retention time) (YMC S5ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 406.21 [M+H]⁺.

EXAMPLE 476(3aαc,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[2-(trifluoromethyl)-4-benzoxazolyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(476D)

A. 4-Nitro-2-trifluoromethylbenzoxazole (476A)

2-Amino-3-nitrophenol (10.00 g, 64.88 mmol) was added to 100 mL ofvigorously stirring trifluoroacetic anhydride and the resulting mixturewas stirred at room temperature for 12 h. The solvent was removed invacuo to give a dark blue solid which was dissolved in 200 mL of CH₂Cl₂and washed sequentially with 10% NaOH (2×100 mL), water (100 mL), brine(100 mL), and dried over MgSO₄. Filtration and concentration in vacuogave compound 476A (10.78 g, 72%) as a brown solid. No furtherpurification was required. HPLC: 92.9% at 2.43 min (retention time) (YMCS5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

B. 4-Amino-2-trifluoromethylbenzoxazole (476B)

Compound 476A (10.75 g, 46.30 mmol) was dissolved in 1:1 EtOAc/10% HOAc(250 mL) and heated to 65° C. Iron powder (12.93 g, 231.5 mmol) wasadded portionwise and the reaction was stirred for 6 h at 65° C. Aftercooling, the mixture was filtered through Celite rinsing with EtOAc. Theorganic layer was separated, washed with H₂O (3×100 mL), brine (100 mL),dried over MgSO₄, and concentrated in vacuo to give a brown oil. Thecrude material was purified by flash chromatography on silica geleluting with 70/30 CH₂Cl₂/hexanes to give compound 476B (7.02 g, 75%) asa yellow crystalline solid. HPLC: 96.7% at 2.68 min (retention time)(YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

C. 1-(2-Trifluoromethyl-benzoxazol-4-yl)-pyrrole-2,5-dione (476C)

Compound 476B (0.500 g, 2.48 mmol) was dissolved in acetic acid (10 mL)and maleic anhydride (0.267 g, 2.72 mmol) was added. The mixture washeated at reflux for 3 h, cooled and the solvent removed in vacuo togive a tan solid. The crude product was purified by flash chromatographyon silica gel eluting with 2% MeOH/CH₂Cl₂ to give compound 476C (0.40 g,57%) as an off-white solid. HPLC: 89.7% at 2.38 min (retention time)(YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).MS (ES): m/z 283.21 [M+H]⁺.

D.(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[2-(trifluoromethyl)-4-benzoxazolyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(476D)

Compound 476C (0.24 g, 0.85 mmol) and 2,5-dimethylfuran (0.132 g, 1.37mmol) were combined in 3 mL of benzene in a sealed tube and heated at60° C. for 12 h. The mixture was cooled and concentrated in vacuo togive a yellow oil which was dissolved in 1/1 EtOAc/EtOH (6 mL). 10% Pd/C(100 mg) was added and the mixture was stirred under an H₂ balloon for3.5 h. The reaction was filtered through Celite and the solvent removedin vacuo to give the crude product as a pale yellow oil. Purification byflash chromatography on silica gel eluting with 2% Et₂O/CH₂Cl₂ gave0.107 g (33%) of compound 476D as a white foam. HPLC: 96.5% at 2.80 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 381.17 [M+H]⁺.

EXAMPLE 477(3aα,4β,7β,7aα)-2-Methyl-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-7-benzoxazolecarbonitrile(477E)

A. 2-Cyano-5-nitrophenol (477A)

3,4-Methylenedioxynitrobenzene (1.67 g, 10.0 mmol) was dissolved in 20mL of HMPA and sodium cyanide (0.49 g, 10.0 mmol) was added. Thereaction was heated to 150° C. under nitrogen and three portions ofsodium cyanide (0.245 g, 5.00 mmol, total) were added over 15 min. Thereaction was maintained at 150° C. for 45 min, cooled, and poured into50 mL of H₂O followed by the addition of 50 mL of 5% NaOH. The aqueouslayer was extracted with ether (2×25 mL) and the organic layer wasdiscarded. The basic aqueous layer was carefully acidified to pH 4 byaddition of 10% HCl and extracted with ether (3×25 mL). The combinedorganic layers were washed with brine (25 mL), dried over sodium sulfateand concentrated in vacuo. Purification by flash chromatography onsilica gel eluting with 5% MeOH/CH₂Cl₂ gave 1.05 g (64%) of compound477A as a yellow-brown solid. HPLC: 91.6% at 1.03 min (retention time)(Phenomenex column, 30×4.6 mm, 10-90% aqueous methanol over 2mincontaining 0.1% TFA, 5 mL/min, monitoring at 220 nm. MS (ES): m/z165.23 [M+H]⁺.

B. 2-Amino-4-cyano-3-hydroxynitrobenzene (477B)

Compound 477A (0.438 g, 2.67 mmol) was dissolved in 25 mL of DMSO andtrimethylhydrazinium iodide (0.534 g, 2.67 mmol) was added. Sodiumpentoxide (0.880 g, 8.01 mmol) was added under N₂ to give a deep redsolution and stirring was continued overnight at rt. The reactionmixture was poured into 50 mL of 10% HCl and extracted with EtOAc (2×25mL). The combined organic layers were washed with water (25 mL), brine(25 mL), dried over sodium sulfate and concentrated in vacuo to givecompound 477B as an oily red solid which was used directly in the nextreaction without further purification.

C. 7-Cyano-2-methyl-4-nitrobenzoxazole (477C)

Compound 477B (0.360 g, 2.01 mmol) and triethyl orthoacetate (1.30 g,8.04 mmol) were combined and heated at reflux under nitrogen for 1 h.The solvent was removed in vacuo and the resulting residue purified byflash chromatography eluting with 5% ether/CH₂Cl₂ to give 0.255 g (63%)of compound 477C as a brown solid. HPLC: 98.4% at 1.80 min (retentiontime) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoringat 220 nm). MS (ES): m/z 204.28 [M+H]⁺.

D. 4-Amino-7-cyano-2-methylbenzoxazole (477D)

Compound 477C (0.156 g, 0.77 mmol) was dissolved in a 1:1 mixture ofEtOAc/10% HOAc (20 mL) and heated to 65° C. Iron powder (325 mesh, 0.214g, 3.83 mmol) was added and the reaction was stirred for 4 h. The cooledmixture was filtered through Celite and the resulting filtrate waswashed with water (25 mL), brine (25 mL), dried over MgSO₄, andconcentrated to give compound 477D (0.118 g, 89%) as an orange solid.HPLC: 87% at 2.03 min (retention time) (YMC S5 ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 174.05[M+H]⁺.

E.(3aα,4β,7β,7aα)-2-Methyl-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-7-benzoxazolecarbonitrile(477E)

Compound 477D (0.060 g, 0.35 mmol) and compound 20A (0.071 g, 0.37 mmol)were combined in a sealed tube with toluene (2 mL), triethylamine (0.24mL, 1.7 mmol), and MgSO₄ (0.104 g, 0.866 mmol). The sealed tube washeated at 135° C. for two days. The cooled reaction mixture was dilutedwith EtOAc, filtered, and concentrated in vacuo to give crude product asa brown oil. Purification by flash chromatography on silica gel elutingwith 1/1 EtOAc/hexanes gave 0.014 g (12%) of compound 477E as anoff-white solid. HPLC: 96.5% at 2.27 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 352.23 [M+H]⁺.

EXAMPLE 478(3aα,4β,5β,7β,7aα)-4-[7-[2-(4-Cyanophenoxy)ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,slow eluting enantiomer (478)

n-BuLi (0.050 mL, 1.6 M, 0.075 mmol) was added to a solution of compound244ii (33.7 mg, 0.0683 mmol) in THF (1.0 mL) at −78° C. under argon. Thereaction mixture was warmed to room temperature and methylfluorosulfonate (0.010 mL, 0.12 mmol) was added dropwise. Once startingmaterial was consumed, as was evident by HPLC, the reaction was quenchedwith H₂O and the resulting aqueous mixture was extracted with CH₂Cl₂(3×5 mL). The combined organic layers were dried over MgSO₄ andconcentrated under reduced pressure. Purification by reverse phasepreparative HPLC [22.09 min (YMC S5 ODS column, 20×100 mm, 0-100%aqueous methanol over 25 mincontaining 0.1% TFA, 20 mL/min, monitoringat 220 nm)] gave 13.0 mg (38%) of compound 478 as a white solid. HPLC:93% at 3.35 min (YMC S5 ODS column, 4.6×50 mm, 10-90% aqueous methanolover 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ES): m/z 508.17 [M+H]⁺.

EXAMPLE 479(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(2-methyl-6-benzoxazolyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(479B)

A. 2-Methyl-6-aminobenzoxazole (479A)

To a solution of 2-methyl-6-nitrobenzoxazole (100 mg, 0.560 mmol) inAcOH (2 mL) was added iron powder (325 mesh, 63.0 mg, 1.12 mmol) at 70°C. in a single portion. After 15 min at 70° C. additional iron powder(325 mesh, 63.0 mg, 1.12 mmol) was added and stirring was continued for15 min. The mixture was cooled and concentrated under reduced pressure.The resulting residue was taken up into EtOAc and washed with sat.Na₂CO₃ followed by H₂O. The organic layer was dried over MgSO₄,concentrated under reduced pressure and purified by flash chromatographyon silica gel eluting with a gradient of 0 to 25% EtOAc in CH₂Cl₂ toyield 69 mg (83%) of compound 479A as a solid. HPLC: 97% at 0.24 min(retention time) (YMC S5 ODS column, 4.6×50 mm Ballistic, 10-90% aqueousmethanol over 4 min containing 0.2% H₃PO₄, 4 mL/min, monitoring at 220nm). MS (ES): m/z 149.2 [M+H]⁺.

B.(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(2-methyl-6-benzoxazolyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(479B)

Compound 479A (30 mg, 0.20 mmol), MgSO₄ (60 mg, 0.50 mmol),triethylamine (140 μL, 1.00 mmol) and compound 20A (45 mg, 0.23 mmol)were taken up in 0.25 mL of toluene and placed in a sealed tube. Thesealed tube was heated at 135° C. for 14 h and the reaction was allowedto cool to rt. The mixture was filtered through a short pad of Celite,eluting with MeOH and the solvent was removed in vacuo. The residue waspurified by flash chromatography on silica gel eluting with a gradientof 0 to 50% EtOAc in CH₂Cl₂ to give 49 mg (65%) of compound 479B as atan solid. HPLC: 98% at 2.30 min (retention time) (YMC S5 ODS column,4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z326.9 [M+H]⁺.

EXAMPLE 480(3aα,4β,7β,7aα)-2-(2,1,3-Benzoxadiazol-5-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(480B)

A. 5-Amino-2,1,3-benzoxadiazole (480A)

To a solution of 2,1,3-benzoxadiazole-5-carboxylic acid (102 mg, 0.621mmol) in THF (3 mL) was added triethylamine (103 μL, 0.739 mmol)followed by DPPA (160 μL, 0.739 mmol) at room temperature. The mixturewas stirred for 4 h, diluted with CH₂Cl₂ and washed with water. Theorganic layer was dried over MgSO₄, concentrated and purified by flashchromatography on silica gel with 0 to 50% EtOAc in CH₂Cl₂. Theresulting material was dissolved in AcOH (2 mL) and water (0.7 mL) wasadded dropwise yielding a slightly cloudy solution which was heated at105° C. for 30 min. The mixture was cooled, made basic with sat. Na₂CO₃solution and extracted several times with THF. The combined organiclayers were dried over MgSO₄, concentrated and purified by flashchromatography on silica gel eluting with 0 to 15% MeOH in CH₂Cl₂ togive 34 mg (41%) of compound 480A as a yellow solid. HPLC: 100% at 1.27min (retention time) (YMC S5 ODS column, 4.6×50 mm Ballistic, 10-90%aqueous methanol over 4 mincontaining 0.2% H₃PO₄, 4 mL/min, monitoringat 220 nm). MS (ES): m/z 136.0 [M+H]⁺.

B.(3aα,4β,7β,7aα)-2-(2,1,3-Benzoxadiazol-5-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(480B)

Compound 480A (34 mg, 0.25 mmol), MgSO₄ (76 mg, 0.63 mmol),triethylamine (180 μL, 1.26 mmol) and compound 20A (74 mg, 0.38 mmol)were dissolved in 0.25 mL of toluene and placed in a sealed tube. Thesealed tube was heated at 135° C. for 14 h. The cooled reaction mixturewas filtered through a short pad of Celite, eluting with acetone and thesolvent was removed in vacuo. The residue was purified by reverse phasepreparative HPLC (YMC S5 ODS 20×100 mm, eluting with 30-100% aqueousmethanol over 10 mincontaining 0.1% TFA, 20 mL/min). Concentration ofthe desired fractions afforded a residue which was partitioned betweenCH₂Cl₂ and sat. NaHCO₃ solution. The aqueous layer was extracted oncewith CH₂Cl₂ and the combined organic phases were dried over Na₂SO₄.Concentration under reduced pressure gave 42 mg (53%) of compound 480Bas a yellow solid. HPLC: 100% at 2.62 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). ¹HNMR (400 MHz, CDCl₃) δ=7.91 (d, 1H), 7.90 (dd, 1H), 7.37 (dd, 1H), 3.09(s, 2H), 1.85 (s, 4H), 1.67 (s, 6H).

EXAMPLE 481[3aR-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-[(5-chloro-2-pyridinyl)oxy]ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(481D) &[3aS-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-[(5-chloro-2-pyridinyl)oxy]ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(481E)

A. 1-Benzothiazol-6-yl-pyrrole-2,5-dione (481A)

A mixture of 5-aminobenzothiazole (2.00 g, 13.3 mmol) and maleicanhydride (1.96 g, 20.0 mmol) in AcOH (27 mL) was heated at 115° C. for20 h. The mixture was cooled and concentrated under reduced pressure.The residue was taken up in THF and washed with saturated Na₂CO₃. Theaqueous layer was extracted several times with THF and the combinedorganic layers were dried over MgSO₄. Purification by flashchromatography on silica gel eluting with 0 to 50% EtOAc in CH₂Cl₂ gave1.37 g (45%) of compound 481A as a pale yellow solid. HPLC: 100% at 2.62min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 231.0 [M+H]⁺.

B.(3aα,4β,7β,7aα)-2-(6-Benzothiazolyl)-4-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-3a,4,7,7a-tetrahydro-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(481B)

A suspension of compound 481A (445 mg, 1.93 mmol) and compound 204A (929mg, 3.87 mmol) in benzene (2 mL) was heated to 60° C. and acetone wasadded until a clear solution was obtained. The resulting mixture wasstirred at 60° C. for 24 h and was then slowly concentrated in vacuo.The resulting residue was dissolved in acetone and slowly concentratedin vacuo. This process was repeated a total of three times. Purificationby flash chromatography on silica gel eluting with 0 to 30% acetone inhexanes gave 820 mg (90%) of compound 481B as a white solid. HPLC: 100%at 2.62 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 471.3 [M+H]⁺.

C.[3aR-(3aαc,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(481Ci) &[3aS-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(481Cii)

To a solution of compound 481B (75 mg, 0.16 mmol) in THF (1 mL) wasadded Wilkinson's catalyst (32 mg, 0.030 mmol) and catecholborane (1.0 Min THF, 1.6 mL, 1.6 mmol) at room temperature under nitrogen. Theresulting mixture was stirred for 2.5 h before it was cooled to 0° C.EtOH (5 mL), 3 N NaOH (2 mL) and H₂O₂ (30%, 1 mL) were addedsequentially, and the mixture was stirred for 2 h at 0° C. The reactionwas quenched by the addition of cold 10% Na₂SO₃ solution (excess)followed by water. The aqueous layer was extracted several times withCH₂Cl₂ and the combined organic layerss were dried over Na₂SO₄.Concentration under reduced pressure followed by purification by flashchromatography on silica gel eluting with 0 to 100% EtOAc in hexanesgave 13 mg (17%) of a racemic mixture of compounds 481Ci & 481Cii as atan solid. HPLC: 96% at 3.58 min (retention time) (YMC S5 ODS column,4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 min containing 0.2%H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 489.3 [M+H]⁺. Theracemic mixture was separated into its individual enantiomers by normalphase preparative chiral HPLC (CHIRALPAK AD 5×50 cm column; eluting with20% MeOH/EtOH (1:1) in heptane (isocratic) at 50 mL/min) to give thefaster eluting enantiomer, compound 481Ci: (Chiral HPLC: 9.40 min;CHRALPAK AD 4.6×250 mm column; eluting with 20% MeOH/EtOH (1:1) inheptane at 1 mL/min) and the slower eluting enantiomer, compound 481Cii:(Chiral HPLC: 10.47 min; CHIRALPAK AD 4.6×250 mm column; eluting with20% MeOH/EtOH (1:1) in heptane at 1 mL/min). The absolute conformationfor compounds 481Ci & 481Cii was not established. For simplicity innomenclature, compound 481Ci is designated herein as having an “R”configuration and compound 481Cii as having an “S” configuration.Enantiomerically pure products derived from compound 481Ci aredesignated herein as having a “R” configuration and enantiomericallypure products derived from compound 481Cii are designated herein ashaving an “S” configuration.

D.[3aR-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-[(5-chloro-2-pyridinyl)oxy]ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(481D)

Compound 481Ci (84 mg, 0.17 mmol) was suspended into EtOH (2 mL) andconc. HCl (40 μL) was added at room temperature. The mixture was stirredfor 15 min before several drops of sat. NaHCO₃ solution were added.Concentration under reduced pressure yielded a residue which waspartitioned between CH₂Cl₂ and sat. NaHCO₃ solution. The aqueous layerwas extracted several times with CH₂Cl₂ and finally with EtOAc. Thecombined organic phases were dried over Na₂SO₄, concentrated andpurified by preparative TLC eluting with 50% acetone in CHCl₃. Thisprocedure served to remove the TBS group from compound 481Ci, yieldingthe free primary alcohol. A 12 mg (0.03 mmol) portion of the freealcohol of compound 481Ci was reacted with 5-chloro-2-pyridinol (8 mg,0.06 mmol), PPh₃ (17 mg, 0.060 mmol) and di-tert-butylazodicarboxylate(15 mg, 0.060 mmol) in THF (0.5 mL) according to the general proceduredescribed in Example 244. The mixture was stirred for 24 h at roomtemperature, diluted with 1N NaOH and the aqueous layer was extractedseveral times with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, concentrated and purified by preparative TLC, eluting with 25%acetone in CHCl₃ to give 9 mg (58%) compound 481D as a white solid.HPLC: 98% at 2.94 min (retention time) (YMC S5 ODS column, 4.6×50 mmBallistic, 10-90% aqueous methanol over 4 mincontaining 0.2% H₃PO₄, 4mL/min, monitoring at 220 rm). MS (ES): m/z 486.2 [M+H]⁺.

E.[3aS-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-[(5-chloro-2-pyridinyl)oxy]ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(481E)

As described in Example 481D, compound 481Cii (58 mg, 0.12 mmol) wastreated with EtOH (2 mL) containing 12 N HCl (40 μL) to yield the freeprimary alcohol product of compound 481Cii. A 15 mg (0.040 mmol) of thefree alcohol of compound 481Cii was reacted with 5-chloro-2-pyridinol(10 mg, 0.080 mmol), PPh₃ (21 mg, 0.080 mmol) anddi-tert-butylazodicarboxylate (18 mg, 0.080 mmol) in THF (0.5 mL) in themanner described above and the resulting product was purified asdescribed above to yield 8 mg (41%) of compound 481E as a white solid.HPLC: 99% at 2.93 min (retention time) (YMC S5 ODS column, 4.6×50 mmBallistic, 10-90% aqueous methanol over 4 mincontaining 0.2% H₃PO₄, 4mL/min, monitoring at 220 nm). MS (ES): m/z 486.2 [M+H]⁺.

EXAMPLE 482[3aR-(3aα,4β,5β,7β,7aα)]-7-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(482F) &[3aS-(3aα,4β,5β,7β,7aα)]-7-[7-[2-[(5-Chloro-2-Pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(482G)

A.7-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-benzo[1,2,5]thiadiazole-4-carbonitrile(482A)

Maleic anhydride (667 mg, 6.80 mmol) was added to a solution of compound424A (600 mg, 3.41 mmol) in THF (9 mL). The mixture was heated at 110°C. for 10 h. The reaction was concentrated under reduced pressure andacetic anhydride (1 mL) was added to the residue. The reaction mixturewas heated at 75° C. for 30 min and then cooled to rt. Purification byflash chromatography on silica gel eluting with 3% acetone/CHCl₃ gave758 mg (2.96 mmol, 67%) of compound 482A. HPLC: 97% at 1.98 min(retention time) (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4min gradient with 0.2% H₃PO₄, monitoring at 220 nm). MS (ES): m/z 257.01[M+H]⁺.

B.(3aα,4β,7β,7aα)-7-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-1,3,3a,4,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(482B)

A solution of compound 482A (758 mg, 2.96 mmol) and compound 204A (711mg, 2.96 mmol) in benzene (2 mL) and acetone (2 mL) was heated at 60° C.for 6 h. The reaction mixture was concentrated in vacuo at 42° C. for 40min to give 1.5 g of crude compound 482B, which was used directly in thenext step without further purification.

C.(3aα,4β,5β,7β,7aα)-7-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(482C)

Borane-dimethylsulfide complex (0.66 mL, 6.96 mmol) was added to asolution of compound 482B (1.15 g, 2.32 mmol) in THF (6 mL) at 0° C.After stirring at 0° C. for 2 h, the reaction mixture was quenched withphosphate buffer (60 mL, pH 7.2) and then EtOH (35 mL), H₂O₂ (8 mL, 30%aq.) and THF (4 mL) were added. The reaction mixture was stirred at 0°C. for 1 h and was then extracted with CH₂Cl₂ (4×100 mL). The combinedorganic layers were washed with 10% aq. Na₂SO₃ (1×160 mL) followed bybrine (1×160 mL) and dried over Na₂SO₄. Purification by flashchromatography on silica gel eluting with 10% acetone/CHCl₃ gave 250 mg(0.486 mmol, 21%) of compound 482C as an orange solid. HPLC: 85% at 3.70min (retention time) (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanolover 4 min gradient with 0.2% H₃PO₄, monitoring at 220 nm). MS (ES): m/z515.27 [M+H]⁺.

D.[3aR-(3aα,4β,5β,7β,7aα)]-7-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile&[3aS-(3aα4β,5β,7β,7aα)]-7-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(482Di & 482Dii)

The racemic compounds 482C was separated by normal phase preparativechiral HPLC using a Chiracel OD column (5 cm×50 cm), eluting with 10%EtOH in hexane at 50 mL/min to give the faster eluting compound 482Di(Chiral HPLC: 11.89 min; CHIRALCEL OD 4.6×250 mm column; isocraticelution with 12% EtOH in hexane at 2 mL/min) and the slower elutingcompound 482Dii (Chiral HPLC: 16.10 min; CHIRALCEL OD 4.6×250 mm column;isocratic elution with 12% EtOH in hexane at 2 mL/min). The absoluteconformation for compounds 482Di & 482Dii was not established. Forsimplicity in nomenclature, compound 482Di is designated herein ashaving an “R” configuration and compound 482Dii as having an “S”configuration. Enantiomerically pure products derived from compound482Di are designated herein as having a “R” configuration andenantiomerically pure products derived from compound 482Dii aredesignated herein as having an “S” configuration.

E.[3aR-(3aα,4β,5β,7β,7aα)]-7-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(482Ei) &[3aR-(3aα,4β,5β,7β,7aα)]-7-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(482Eii)

Compound 482Di (91 mg, 0.18 mmol) was dissolved in 2% 12 N HCl/EtOH (3.0mL) and the mixture was stirred at rt for 20 min. Cold sat. NaHCO₃ wasadded to the mixture until it was basic (pH 8). The reaction wasextracted with EtOAc. The organic layers were then washed with brine anddried over anhydrous sodium sulfate. Concentration in vacuo gave 73 mg(0.18 mmol, 100%) compound 482Ei as a yellow solid which was notpurified further. HPLC: 95% at 1.73 min (retention time) (YMC S5 ODS4.6×50 mm, 10%-90% aqueous methanol over 4 min gradient with 0.2% H₃PO₄,monitoring at 220 nm). MS (ES): m/z 401.13 [M+H]⁺.

Compound 482Dii (90 mg, 0.17 mmol) was dissolved in 2% 12 N HCl/EtOH(3.0 mL) and the mixture was stirred at rt for 20 min. Cold sat. NaHCO₃was added to the mixture until it was basic (pH 8). The reaction wasextracted with EtOAc. The organic layers were then washed with brine anddried over anhydrous sodium sulfate. Concentration in vacuo gave 70 mg(0.17 mmol, 100%) compound 482Eii as an orange solid which was notpurified further. HPLC: 90% at 1.74 min (retention time) (YMC S5 ODS4.6×50 mm, 10%-90% aqueous methanol over 4 min gradient with 0.2% H₃PO₄,monitoring at 220 nm). MS (ES): m/z 401.14 [M+H]⁺.

F.[3aR-(3aα,4β,5β,7β,7aα)]-7-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(482F)

DBAD (21 mg, 0.090 mmol) was added to a solution of PPh₃ (24 mg, 0.090mmol) in THF (0.4 mL). After stirring for 10 min, 5-chloro-2-pyridinol(12 mg, 0.090 mmol) was added and the reaction mixture was stirred foran additional 5 min. Compound 482Ei (18 mg, 0.045 mmol) was added andthe mixture was stirred at rt for 1 h. The reaction was thenconcentrated under reduced pressure. Purification by preparative TLCeluting with 20% acetone/CHCl₃ gave 12 mg (0.023 mmol, 52%) of compound482F. HPLC: 98% at 3.15 min (retention time) (YMC S5 ODS 4.6×50 mm,10%-90% aqueous methanol over 4 min gradient with 0.2% H₃PO₄, monitoringat 220 nm). MS (ES): m/z 512.11 [M+H]⁺.

G.[3aS-(3aα,4β,5β,7β,7aα)]-7-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile(482G)

DBAD (21 mg, 0.090 mmol) was added to a solution of PPh₃ (24 mg, 0.090mmol) in THF (0.4 mL). After stirring for 10 min, 5-chloro-2-pyridinol(12 mg, 0.090 mmol) was added and the reaction mixture was stirred foran additional 5 min. Compound 482Eii (18 mg, 0.045 mmol) was added andthe mixture was stirred at rt for 1 h. The reaction was thenconcentrated under reduced pressure. Purification by preparative TLCeluting with 20% acetone/CHCl₃ gave 11 mg (0.021 mmol, 47.0%) ofcompound 482G. HPLC: 98% at 3.15 min (retention time) (YMC S5 ODS 4.6×50mm, 10%-90% aqueous methanol over 4 min gradient with 0.2% H₃PO₄,monitoring at 220 nm). MS (ES): m/z 512.15 [M+H]⁺.

EXAMPLE 483(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxabicyclo[2,2,1]heptane-1-carboxylicacid,[3aS-(3aα,4β,5β,7β,7aα)]-2-[4-cyano-3-(trifluoromethyl)phenyl]octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindol-5-ylester (483)

To a solution of compound 471Di (25 mg, 0.066 mmol) in 0.25 mL of CH₂Cl₂at rt and under argon, was added a solution of (1S)-(-)-camphanic acid(20 mg, 0.10 mmol) in 0.2 mL of CH₂Cl₂. A solution of DCC (20 mg, 0.10mmol) in 0.25 mL of CH₂Cl₂ was then added followed by DMAP (4.0 mg,0.034 mmol). A white precipitate was obtained immediately and stirringwas continued overnight. The precipitate was removed by filtration andthe filtrate was diluted with EtOAc. The resulting solution was washedwith 1N HCl, brine, sat. NaHCO₃, and brine then dried over MgSO₄.Concentration in vacuo afforded a viscous oily residue. The crudematerial was subjected to flash chromatography on a 20 cm³ column ofsilica gel eluting with 50% EtOAc in hexanes to 32 mg of a white solid.Recrystallization from CH₂Cl₂/hexane yielded 20 mg (86%) of compound 483as large crystals. This material was subjected to X-ray crystaldiffraction studies to elucidate the exact stereochemistry of compound471Di as referenced to the known fixed stereochemistry of the(1S)-(-)-camphanic acid appendage. LCMS: 100% at 1.9 min (retentiontime) (Phenomenex Luna C18 column, 2×30 mm, 0-100% aqueous acetonitrileover 3 min containing 10 mM NH₄OAc at 1 mL/min, monitoring at 220 nm).MS (ESI): m/z 559.3 [M−H]⁻.

EXAMPLE 484 (3aα,4β,5β,7β,7aα)-5-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(484)

To a dry, 3-necked, 25 mL round-bottom was added TiCl₂ Cp₂ (0.500 g,2.01 mmol) and THF (4 mL) to give a deep red solution. Activated zincdust (0.392 g, 6 mmol, prepared as described in Fieser and Fieser,Volume 1, p. 1276) was added and the suspension was stirred for 30 minduring which time the color changed from brick-red to emerald-green. Theunreacted zinc dust was allowed to settle. In a separate 3-necked, 25 mLround-bottom flask was added compound 464F (0.202 g, 0.399 mmol), THF (1mL) and 1,4-cyclohexadiene (0.380 mL, 4.02 mmol). The Ti(III) reagent(0.90 mL, 0.45 mmol) was added via an addition funnel with a cotton plugat the bottom rinsing with THF (1 mL). After 1 h, HPLC showed ˜50%conversion and an additional 0.9 mL (0.45 mmol) of the titanium reagentwas added. After 1 h, HPLC showed complete consumption of startingmaterial. Saturated ammonium chloride (5 mL) was added, followed by 10mL of EtOAc. The organic layer was separated, washed with brine (5 mL),dried over Na₂SO₄, and concentrated in vacuo to give the crude productas an orange semi-solid. The crude material was purified by flashchromatography on silica gel eluting with 50% CH₂C12/48% EtOAc/2% MeOHto give 0.10 g (59%) of compound 484 as a light yellow foam. HPLC: 91%at 3.65 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 508.27 [M+H]⁺.

EXAMPLE 485[3aR-(3aα,4β,5β,7β,7aα)]-5-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(485i) &[3aS-(3aα,4β,5β,7β,7aα)]-5-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(485ii)

The racemic compound 484, was separated into its individual antipodes bynormal phase preparative chiral HPLC. A Chiralcel OD column (50×500 mm)was used with a flow rate of 50 mL/min (20% EtOH/hexanes) monitoring at220 nm. The faster eluting antipode, compound 485i had a retention timeof 35.8 min and the slower antipode, compound 485ii had a retention timeof 49.7 min. Both antipodes were isolated as white solids afterseparation. Compound 485i: HPLC: 100% at 4.980 min (retention time)(Chiracel OD column (5×50 mm), 2.0 mL/min, 20% EtOH/hexanes, monitoringat 220 nm), >99% ee. MS (ES): m/z 508.23 [M+H]⁺. Compound 485ii: HPLC:98.6% at 7.357 min (retention time) (Chiracel OD column (5×50 mm), 2.0mL/min, 20% EtOH/hexanes, monitoring at 220 nm), 97.2% ee. MS (ES): m/z508.21 [M+H]⁺. The absolute conformation for compounds 485i & 485ii wasnot established. For simplicity in nomenclature, compound 485i isdesignated herein as having an “R” configuration and compound 485ii ashaving an “S” configuration. Enantiomerically pure products derived fromcompound 485i are designated herein as having a “R” configuration andenantiomerically pure products derived from compound 485ii aredesignated herein as having an “S” configuration.

EXAMPLE 486[3aR-(3aα,4β,5β,7β,7aα)]-5-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(486i) &[3aS-(3aα,4β,5β,7β,7aα)]-5-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(486ii)

Compounds 485i & 485ii were converted to the free primary alcoholproducts as described in example 466 to give compounds 486i and 486ii aswhite solids.

Compound 486i: HPLC: 98% at 1.650 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 394.21 [M+H]⁺.

Compound 486ii: HPLC: 98% at 1.663 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 394.20 [M+H]⁺.

EXAMPLE 487[3aR-(3aα,4β,7β,7aα)]-5-[7-[2-[(5-Chloro-2-Pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(487)

DBAD (0.088 g, 0.38 mmol) was added to a solution of triphenylphosphine(0.100 g, 0.382 mmol) in THF (1.0 mL) at 22° C. and stirred for 10 min.5-Chloro-2-pyridinol (0.049 g, 0.38 mmol) was added as a solid andstirring was continued for 10 min. The reaction mixture was added tocompound 486i (0.100 g, 0.250 mmol) in THF (1.0 mL). After stirring for3 h, the reaction was concentrated in vacuo and purified by flashchromatography on silica gel eluting with 20-50% acetone/chloroform togive 0.080 g (63%) of compound 487 as a white solid. HPLC: 100% at 3.023min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 505.16 [M+H]⁺.

EXAMPLE 488 [3aS-(3aα,4β,7β,7aα)]-5-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(488)

DBAD (0.088 g, 0.38 mmol) was added to a solution of triphenylphosphine(0.100 g, 0.382 mol) in THF (1.0 mL) at 22° C. and stirred for 10 min.5-Chloro-2-pyridinol (0.049 g, 0.38 mmol) was added as a solid andstirring was continued for 10 min. The reaction mixture was added tocompound 486ii (0.100 g, 0.250 mmol) in THF (1.0 mL). After stirring for3 h, the reaction was concentrated in vacuo and purified by flashchromatography on silica gel eluting with 10-50% acetone/chloroform togive 0.080 g (63%) of compound 488 as a white solid. HPLC: 95% at 3.030min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 505.12 [M+H]⁺.

EXAMPLE 489[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile(489Gi) &[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile(489Gii)

A. 2-Iodo-4-nitro-phenylamine (489A)

To a mixture of iodine (46.0 g, 0.180 mol) and silver sulfate (56.3 g,0.180 mol) in anhydrous ethanol (500 mL) was added 4-nitroaniline (25.0g, 0.180 mol) and the reaction mixture was stirred for 5 h at rt. Theresulting yellow solution was filtered and concentrated in vacuo. Theresulting residue was dissolved into 400 mL ethyl acetate, washed with1N sodium hydroxide solution (2×250 mL), dried over sodium sulfate,filtered, and concentrated in vacuo to yield 45.5 (95%) of compound489A, as a yellow solid. HPLC: 98% at 2.837 min (retention time)(Shimadzu VP-ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanolover 4 min containing 0.1% trifluoracetic acid, 4 mL/min, monitoring at220 nm). MS (ES): m/z 265.08 [M+H]⁺.

B. 2-Iodo-4-nitro-benzonitrile (489B)

Compound 489A (10.0 g, 37.9 mmol) was dissolved in a mixture of 20 mL 12N HCl/40 mL water and then cooled to 0° C. To this mixture was slowlyadded a solution of sodium nitrite (5.23 g, 75.8 mmol) in 10 mL waterwhile maintaining the reaction temperature at 0° C. The reaction wasstirred for 1 h at 0° C. and then slowly added to a mechanically stirredsolution of freshly prepared cuprous cyanide (3.0 g, 33 mmol, preparedas described in Vogel's Textbook of Practical Organic Chemistry, 5^(th)edition, pg. 429) and potassium cyanide (6.30 g, 96.7 mmol) in water (50mL) at 50° C. The reaction was stirred for 1 h at 50° C., cooled to 25°C. and extracted with methylene chloride (2×200 mL). The organic portionwas dried over sodium sulfate, filtered and concentrated in vacuo. Theresulting residue was purified by chromatography on silica gel elutingwith 4:1 hexane:ethyl acetate to yield 4.6 g (44%) of compound 489B asan orange solid. HPLC: 98% at 2.647 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

C. 4-Amino-2-iodo-benzonitrile (489C)

A mixture of compound 489B (4.60 g, 16.8 mmol), tetrahydrofuran (75 mL),ethanol (100 mL), ammonium chloride solution (1.51 g, 28.3 mmol,dissolved in 100 mL of water), and iron (325 mesh, 4.21 g, 75.4 mmol)was mechanically stirred. The reaction mixture was heated to reflux for3 h or until all starting material was consumed. The reaction mixturewas cooled, filtered through Celite and concentrated in vacuo. Theresulting residue was dissolved in ethyl acetate (200 mL) and washedwith 1N sodium hydroxide (2×150 mL), dried over sodium sulfate, filteredand concentrated in vacuo to yield 3.97 g (97%) of compound 489C as adark solid. HPLC: 95% at 1.877 min (retention time) (YMC S5 ODS column,4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z245.13 [M+H]⁺.

D. 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-2-iodo-benzonitrile (489D)

Compound 489C (3.97 g, 16.3 mmol) and maleic anhydride (2.41 g, 24.4mmol) were refluxed in glacial acetic acid (15 mL) for 5 h. The reactionwas cooled to 25° C. and then poured onto ice (100 mL). The resultingprecipitate was isolated by filtration and washed with water (2×25 mL)and dried under vacuum to yield 4.78 g (90%) of compound 489D as a tansolid. HPLC: 82% at 2.68 min (retention time) C Shimadzu VP-ODS column,4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining0.1% trifluoroacetic acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z325.04 [M+H]⁺.

E.(3aα,4β,7β,7aα)-4-(1,3,3a,4,7,7a-Hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile(489E)

A solution of compound 489D (0.40 g, 1.2 mmol) in 2,5-dimethylfuran (2.0g) was stirred at 75° C. for 2 h. The reaction was decanted from anyinsoluble materials and the particulates were washed with diethyl ether.The combined decant and ether washes were combined and concentrated invacuo while maintaining a temperature of <50° C. The resulting residuewas triturated with hexanes to yield 0.56 g (94% based on purity) ofcompound 489E as a tan solid. Due to the propensity of the product toundergo a retro-Diels-Alder reaction, no further purification wasattempted. HPLC: 85% at 3.01 min (retention time) (Shimadzu VP-ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.1% trifluoroacetic acid acid, 4 mL/min, monitoring at254 nm). MS (ES): m/z 421.05[M+H]⁺.

F.(3aα,4β,5β,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile(489F)

To a solution of compound 489E (0.40 g, 0.95 mmol) in dry THF (5 mL)cooled to 0° C. was added borane-dimethylsulfide complex (0.2 mL, 1.9mmol, 10 M) and the reaction solution was allowed to warm to 25° C.After stirring for 30 min, the reaction was cooled to 0° C. and pH 7phosphate buffer (6.6 mL) was slowly added, followed by the addition of30% hydrogen peroxide (0.7 mL). The reaction was stirred at 25° C. for 1h and then partitioned between ethyl acetate (100 mL) and water (100mL). The organic portion was isolated, dried over sodium sulfate,filtered and concentrated in vacuo. The resulting residue was purifiedby silica gel eluting with 3:1 methylene chloride:ethyl acetate to yield0.11 g (25%) of compound 489F as a white solid. HPLC: 99% at 2.527 min(retention time) (Shimadzu VP-ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.1% trifluoroacetic acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 439.09 [M+H]⁺.

G.[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile(489Gi) &[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile(489Gii)

The racemic compounds 489F, was separated into its individual antipodesby normal phase preparative chiral HPLC. A Chiralcel AD column (50×500mm) was used with a flow rate of 50 mL/min (70% Isopropanol/hexanes)monitoring at 220 nm. The faster eluting antipode, compound 489Gi had aretention time of 4.587 min and the slower eluting antipode, compound489Gii had a retention time of 6.496 min. Both antipodes were isolatedas white solids after separation. The absolute conformation forcompounds 489Gi & 489Gii was not established. For simplicity innomenclature, compound 489Gi is designated herein as having an “R”configuration and compound 489Gii as having an “S” configuration.

EXAMPLE 490(3aα,4β,5β,7β,7aα)-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(490B)

A.(3aα,4β,7β,7aα)-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(490A)

A mixture of triphenylphosphine (166 mg, 0.633 mmol) and DBAD (146 mg,0.633 mmol) was dissolved in THF (4 mL) under nitrogen and the yellowsolution was stirred for 10 min. 5-Chloro-pyridin-2-ol (82 mg, 0.63mmol) was added and the mixture was stirred for 5 min after whichcompound 242B (165 mg, 0.327 mmol) was added. The mixture was stirredfor 12 h and the solvent was removed under a stream of nitrogen. Theresulting oil was adsorb onto silica gel (1 g) and purified by flashchromatography on a Jones Chromatography silica cartridge (5 g/25 mL)eluting with a gradient of 0-50% acetone in chloroform to give 79.4 mg(47%) of compound 490A as a white foam. HPLC: 99% at 3.48 min (retentiontime) (Phenomenex ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm).MS (ES): m/z 504.17 [M+H]⁺.

B.(3aα,4β,5β,7β,7aα)-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(490B)

Compound 490A (24 mg, 0.048 mmol) was dried into a 1 dram vial with amagnetic stir bar. Silver oxide (57 mg, 0.24 mmol), CH₃CN (500 μL) andiodomethane (20 μL, 0.32 mmol) were added under nitrogen and the mixturewas put in a heated block (82° C.) and stirred for 14 h. The mixtureturned brown after 20 min then green. The mixture was filtered throughCelite and Florisil and was purified by reverse phase preparative HPLC(Shimadzu Shimpac VP ODS column, 20×50 mm, 0-100% aqueous methanol over6 mincontaining 0.1% TFA, monitoring at 220 nm) to give 6.9 mg (28%) ofcompound 490B as a white foam. HPLC: 99% at 3.64 min, 3.76 min(atropisomers, retention time) (Phenomenex ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.1% TFA, 4mL/min, monitoring at 220 nm). MS (ES): m/z 518.19 [M+H]⁺.

EXAMPLE 491[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,(491Ci) &[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(5-Chloro-2-oxo-1(2H)-pyridinyl)ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(491Cii)

A.(3aα,4β,5β,7β,7aα)-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(491A)

Compound 243Cii (142 mg, 0.280 mmol) was dried into a 1 dram vialequipped with a magnetic stir-bar and a Teflon lined cap. Silver oxide(324 mg, 1.40 mmol), CH₃CN (3 mL) and iodomethane (90 μL, 1.4 mmol) wereadded under nitrogen and the mixture was put in a heated block (82° C.).The reaction was stirred overnight, then filtered through Celite andconcentrated in vacuo. The resulting residue was purified by flashchromatography on silica gel eluting with a gradient of 0-50% acetone inchloroform to yield 62.2 mg (43%) of compound 491A. HPLC: 99% at 3.87 &3.95 min (atropisomers, retention time) (Phenomenex ODS column, 4.6×50mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.1% TFA,4 mL/min, monitoring at 220 nm). MS (ES): m/z 521.37 [M+H]⁺.

B.3aα,4β,5β,7β,7aα)-4-[Octahydro-7-(2-hydroxyethyl)-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(491B)

Compound 491A (62.2 mg, 0.119 mmol) was dissolved in ethanol (2 mL) and12 N hydrochloric acid (50 μL) was added and the mixture was stirred for10 min. The solvent was removed in vacuo and the product was purified byflash chromatography on silica gel eluting with a gradient of 0-20%acetone in chloroform to yield 40.3 mg (83%) of compound 491B as a whitesolid. HPLC: 96% at 2.30 & 2.45 min (atropisomers, retention time)(Phenomenex ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanolover 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES):m/z 407.22 [M+H]⁺.

C.[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,slow eluting enantiomer (491Ci) &[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(5-Chloro-2-oxo-1(2H)-pyridinyl)ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(491Cii)

Triphenylphosphine (40 mg, 0.15 mmol) and DBAD (35 mg, 0.15 mmol) weredissolved in THF under nitrogen and stirred 10 min. 5-Chloropyridin-2-ol(20 mg, 0.15 mmol) was added and the mixture was stirred for 5 min.Compound 491B (40.3 mg, 0.0991 mmol) was added and the resulting mixturewas stirred for 2.5 h. The solvent was concentrated in vacuo and theresulting residue was purified by chromatography over Florisil (1.3 g)eluting with a gradient of 0-40% acetone in chloroform to give 140 mg ofa mixture of 491Ci, 491Cii and DBAD. The oil was suspended indichloromethane (3 mL) and trifluoroacetic acid (2 mL) was added. After45 min, the solvent was removed in vacuo and the resulting oil waspartitioned between saturated sodium bicarbonate (20 mL) and EtOAc (20mL). The aqueous layer was extracted with EtOAc (2×20 mL) and thecombined organic layers were dried over magnesium sulfate. Purificationby reverse phase preparative HPLC (Shimadzu Shimpac VP ODS column, 20×50mm, 0-100% aqueous methanol over 6 mincontaining 0.1% TFA, monitoring at220 nm) gave 22 mg (44%) of compound 491Ci and 4.6 mg (9% yield) ofcompound 491Cii. Compound 491Ci: HPLC: 95% at 3.50 min (retention time)(Phenomenex ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanolover 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES):m/z 518.28 [M+H]⁺. Compound 491Cii: HPLC: 85% at 2.94 & 3.07 min(atropisomers, retention time) (Phenomenex ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.1% TFA, 4mL/min, monitoring at 220 nm). MS (ES): m/z 518.27 [M+H]⁺.

EXAMPLE 492[3aR-(3aα,4β,5β,7β,7aα)]-4-[5-(Acetyloxy)-7-[2-[(5-chloro-2-pyridinyl)oxy]ethyl]octahydro-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,slow eluting enantiomer (492)

Acetyl chloride (25 μL, 0.35 mmol) was added to a solution of compound490A (30 mg, 0.060 mmol) in pyridine (600 μL). The mixture was stirredovernight, diluted with hydrochloric acid (0.5 N, 10 mL), extracted withchloroform (3×7 mL). The organic layers were combined, washed with water(3×4 mL) and brine (4 mL), dried over magnesium sulfate and concentratedin vacuo. Purification by flash chromatography on silica gel elutingwith a gradient of 0-50% acetone in chloroform gave 17 mg (53%) ofcompound 492. HPLC: 99% at 3.48 & 3.63 min (atropisomers, retentiontime) (Phenomenex ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm).MS (ES): m/z 546.15 [M+H]⁺.

EXAMPLE 493 Dimethylcarbamic acid,[3aR-(3aα,4β,5β,7β,7aα)]-7-[2-[(5-chloro-2-Pyridinyl)oxy]ethyl]-2-(4-cyano-1-naphthalenyl)octahydro-4-methyl-1,3-dioxo-4,7-epoxy-1H-isoindol-5-ylester, slow eluting enantiomer (493)

To a solution of compound 490A (30 mg, 0.060 mmol) in pyridine (300 μl)was added dimethylcarbamyl chloride (28 μl, 0.30 mmol) and the mixturewas stirred at 25° C. for 12 h. An additional portion ofdimethylcarbamyl chloride (28 μL, 0.30 mmol) was added and the reactionwas heated at 70° C. for 12 h. A third portion of dimethylcarbamoylchloride (28 μl, 0.30 mmol) as well as pyridine (300 μl) were added andthe mixture was stirred at 100° C. for 24 h. The solution was dilutedwith 0.5 N HCl (10 mL) and extracted with chloroform (3×7 mL). Theorganic layers were combined and washed with water (3×4 mL) and brine (4mL), dried over magnesium sulfate and concentrated in vacuo.Purification by reverse phase preparative HPLC (Shimadzu Shimpac VP ODScolumn, 20×50 mm, 0-100% aqueous methanol over 6 mincontaining 0.1% TFA,monitoring at 220 nm) gave 15.7 mg (46%) of compound 493 as a whitesolid. HPLC: 99% at 3.52 min & 3.69 min (atropisomers, retention time)(Phenomenex ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanolover 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES):m/z 575.10 [M+H]⁺.

EXAMPLE 494[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-4-methyl-5-[[(methylamino)carbonyl]oxy]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,slow eluting enantiomer (494)

Methyl isocyanate (36 μL, 0.60 mmol) was added to a solution of compound490A (30 mg, 0.060 mmol) in dioxane (600 μL) and was heated at 80° C.overnight. An additional portion of methyl isocyanate (36 μL, 0.60 mmol)was added and the mixture was heated at 100° C. for 24 h. A thirdportion of methyl isocyanate (36 μL, 0.60 mmol) was added and themixture was stirred at 100° C. for 24 h. The solvent was removed invacuo and the oil was purified by reverse phase preparative HPLC(Shimadzu Shimpac VP ODS column, 20×50 mm, 0-100% aqueous methanol over6 mincontaining 0.1% TFA, monitoring at 220 nm) to give 20 mg (59%) ofcompound 494 as a clear glass. HPLC: 99% at 3.33 min & 3.42 min(atropisomers, retention time) (Phenomenex ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.1% TFA, 4mL/min, monitoring at 220 nm). MS (ES): m/z 561.08 [M+H]⁺.

EXAMPLE 495[3aR(3aα,4β,5β,7β,7aα)]-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(495Ai) &[3aS(3aα,4β,5β,7β,7aα)]-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(495B)

A.[3aS-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(495Ai) &(3aα,4β,5β,7β,7aα)-4-[2-(Acetyloxy)ethyl]-2-(4-cyano-1-naphthalenyl)hexahydro-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(495Aii)

Racemic compound 223B (10.26 g, 27.26 mmol) was dissolved in anhydrousTHF (500 mL) in a 10 L bottle. tert-Butyl methyl ether (4.86 L), vinylacetate (216 mL) and Lipase (108 g, [Sigma, Lipase type II, crude fromPorcine pancreas, product No. L3126, Lot No. 021K1445]) were added. Thereaction mixture was agitated for 24 h at rt and the reaction wasmonitored by HPLC using the following conditions: A 200 μL sample of thereaction mixture was filtered, dried under a stream of nitrogen andsubjected to HPLC analysis (YMC ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol over 4 mincontaining 0.1% TFA, 4 mL/min,monitoring at 220 nm). The reaction was stopped after 60% of thestarting material was consumed. The enzyme was removed by filtration andthe filtrate was concentrated in vacuo. The resulting residue wasdissolved in CHCl₃ and absorbed onto silica gel. Purification by flashchromatography on silica gel eluting with a gradient of 1-5% MeOH inCHCl₃ gave 3.78 g (37%) of compound 495Ai and 6.84 g (60%) of compound495Aii, both as white solids. Compound 495Ai: HPLC: 99% at 3.47 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 min containing 0.1% TFA, 4 mL/min, monitoring at220 nm). MS (ES): m/z 377.09 [M+H]⁺. Normal phase preparative chiralHPLC: 37.8 min (retention time) (chiralpak AD column, 4.6×250 mm, 10micron, 40° C., isocratic elution with 8% EtOH/MeOH (1:1) in heptane,monitoring at 220 nm), 99% ee. Compound 495Aii: HPLC: 99% at 2.92 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at220 nm).

B.[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(495B)

Lipase (134 g, [Sigma, Lipase type II, crude from Porcine pancreas,product No. L3126, Lot No. 021K1445]) was added to 3.5 L of deionizedwater. The mixture was centrifuged to remove most of the suspendedmaterial. The pH of the supernatant was adjusted to 7.06 with 1N sodiumhydroxide and a solution of compound 495Aii (8.04 g, 19.2 mmol) in TBME(1.5 L) was added. The pH was increased to 7.16 by addition of 1N sodiumhydroxide. The reaction mixture was agitated at rt and was monitored byanalytical HPLC as described in Example 495A. After 30 min, the reactionwas filtered through Celite and the filtrate was extracted with ethylacetate (4×1 L) until HPLC showed that all the alcohol has been removed.The organic fractions were combined, dried over magnesium sulfate,filtered and concentrated in vacuo. Purification by flash chromatographyon silica gel (Jones, 50 g column) using a gradient of 0-70% acetone inchloroform followed by 5% MeOH in chloroform gave 2.44 g (33%) ofcompound 495B as a white solid. HPLC: 99% at 2.89 min (retention time)(YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z377.09 [M+H]⁺. Normal phase preparative chiral HPLC: 11.1 min (retentiontime) (chiralpak AD column, 4.6×250 mm, 10 micron, 40° C., isocraticelution with 8% EtOH/MeOH (1:1) in heptane, monitoring at 220 nm), 95%ee.

EXAMPLE 496[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(496Bi) &[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(5-Chloro-2-oxo-1(2H)-pyridinyl)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(496Bii)

A. Preparation of Solid Support (496A)

A mixture of anhydrous CH₂Cl₂ (10 mL) and pyridine (10 mL) was addedunder nitrogen to chlorosulfonylpolystyrene (Argonaut, 1.70 mmol/g, 3.0g, 5.1 mmol) and compound 495Ai (3.78 g, 10.0 mmol) in a polymersynthesis tube. The mixture turned into a yellow gel and was vigorouslyshaken (wrist action shaker for 4 h.). All the solvents were absorbed bythe resin and it looked dry. The resin was washed in portions withCH₂Cl₂ (200 mL) and the washes were combined and extracted with 200 mL1N HCl. The HCl fraction was re-extracted with ethyl acetate (200 mL).The organic fractions were combined and extracted with water (50 mL),brine (50 mL) and the organic fractions were dried over sodium sulfate,filtered and concentrated to give 2.1 g of resin bound compound 496A(89% loaded based on recovered unbound compound 495Ai). The resin waswashed consecutively with DMF (5×), DMF:water (3:1, 5×), THF (3×) andCH₂Cl₂ (3×) (˜30 mL each wash). The resin was dried in vacuo for 1 h toyield 5.35 g of resin. The resin was still wet and was re-treated withthe alcohol. The above described loading process was repeated using therecovered un-reacted compound 495Ai from the above procedure. Recoveredcompound 495Ai (2.1 g, 5.6 mmol) and anhydrous dichloromethane (15 mL)and pyridine (15 mL) and the resin were combined and subjected to thereaction conditions described above. The resulting resin was washed asdescribed previously and dried in vacuo overnight to yield 4.49 g ofresin (87% loaded based on recovered unbound compound 495Ai). Thestarting alcohol was recovered from the dichloromethane:pyridine mixtureas described previously (2.04 g of white solid, which would suggest a92% loading based on recovered alcohol). The resin weigh increase isusually more accurate for loading assessment. The resin loading wascalculated to be 0.87 (determined by resin weight increase)×1.08 mmol/g(calculated 100% loading)=0.94 mmol/g. The resin was used as is for thenext step.

B.[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(496Bi) &[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(5-Chloro-2-oxo-1(2H)-pyridinyl)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(496Bii)

The following procedure describes a general process by which arrays ofcompounds of Formula I can be made using automated approaches.Additional information on such automated synthetic approaches can befound in Example 8. Compounds 496Bi & 496Bii are an example of compoundsmade by such a procedure. For compounds 496Bi & 496Bii,4-chloropyridinol represents the nuceophile reagent. A broaderdefinition of the term nucleophile is contained in the body of thisdocument and is well understood by one skilled in the art. A BohdanMiniReactor equipped with a heating/cooling block was used with 0.5 Dramvials stacked over one another to achieve the same level as the reactortubes. Resin (compound 496A) was measured into the individual vials byusing each Bohdan resin Transfer module plate “10 mg” and “20 mg” once.The weights of resin delivered ranged from 17-23 mg (0.016-0.022 mmol).Cesium carbonate was added using the Bohdan “20 mg” plate whichdelivered ˜57-60 mg (0.17-0.18 mmol). The nucleophiles were weightedinto 1 Dram vials and were diluted in THF to 0.06 M using a Tecan eightchannel liquid handler. The resulting solutions (250 μL, 0.015 mmol)were added manually via a micro-pipette to each of the reaction vialscontaining resin and the resulting array of reaction vials were placedin a Bohdan reactor. When the nucleophiles are amines, 13 μL ofdiisopropylethylamine was added to the THF solution of the amine. Thevials were capped (Teflon-lined) and the reactions were heated withorbital shaking (short stroke 500 rpm) at 70° C. for 24 h. The reactionswere cooled to 25° C. and 1 mL of a mixture of heptane and ethyl acetate(1:1) was added followed by 0.5 mL of water. The organic layer wasextracted manually and individually transferred to a synthesis blocktube containing magnesium sulfate (˜150 mg). The array of synthesisblock tubes were simultaneously filtered and the filtrates wereindividually collected into microtubes (96 well block). The aqueouslayer was re-extracted with 1 mL of a mixture of heptane and ethylacetate (1:1), the organic layer was filtered as described above and thefiltrate was individually collected as described above into the existingmicrotubes.

Analysis of the array of compounds prepared by the above procedure wasperformed using the following automated approach. A 120 μl portion ofeach of the above reaction (filtrates) was aliquoted into two 96 deepwell blocks for analysis. The solvent was concentrated in vacuo and theplates were re-diluted with methanol (500 μL). One plate was analyzed byLCMS (Phenomenex ODS column, 4.6×50 mm, 4 mL/min, gradient 0% A to 100%B (A: 90% water, 10% MeOH, 0.1% TFA; B: A: 90% MeOH, 10% water, 0.1%TFA) and the other by flow-NMR (Varian Inova-500 MHz, MeOH, WET solventsuppression pulse sequence, 128 scans, 60 μl flow cell probe). Thecriteria for submission was: correct molecular ion present and HPLC/NMRpurity >70%. Compounds which did not meet the desired criteria werepurified by reverse phase preparative HPLC (Shimadzu UP-ODS column,20×50 mm, 20 mL/min, gradient 40% B to 100% B in 6 min with 2 min hold(A: 90% water, 10% MeOH, 0.1% TFA; B: A: 90% MeOH, 10% water, 0.1% TFA).HPLC purification yielded 3.4 mg (21%) of compound 496Bi as a glassysolid and 6.8 mg (41%) of compound 496Bii as a glassy solid. Compound496Bi: HPLC: 96% at 3.47 min & 3.62 min (atropisomers, retention time)(Phenominex ODS column, 4.6×50 mm, 4 mL/min, gradient 0% A to 100% B (A:90% water, 10% MeOH, 0.1% TFA; B: A: 90% MeOH, 10% water, 0.1% TFA),monitoring at 220 nm). MS (ES): m/z 487.94 [M+H]⁺. Compound 496Bii:HPLC: 96% at 3.00 min & 3.12 min (atropisomers, retention time)(Phenominex ODS column, 4.6×50 mm, 4 mL/min, gradient 0% A to 100% B (A:90% water, 10% MeOH, 0.1% TFA; B: A: 90% MeOH, 10% water, 0.1% TFA),monitoring at 220 nm). MS (ES): m/z 488.12 [M+H]⁺. Additional compoundsmade by this procedure are set forth in Table 17.

EXAMPLE 497(3aα,4β,5β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(7-methyl-6-benzothiazolyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(497B)

A. 6-Amino-7-methylbenzothiazole (497A)

7-Methyl-6-nitrosobenzothiazole was prepared from 6-nitrobenzothiazoleaccording to the general procedure described by Bartoli et al. Synlett270 (1976). To a solution of 7-methyl-6-nitrosobenzothiazole (889 mg,5.00 mmol) in AcOH (40 mL) at 70° C. was added iron powder (325 mesh,559 mg, 10.0 mmol) in a single portion. The resulting dark reactionmixture was stirred for 15 min before it was cooled and concentrated invacuo to leave a residue which was partitioned between 1N HCl (50 mL)and CH₂Cl₂ (50 mL). The layers were separated and the organic layer waswashed once with 1N HCl (25 mL). The combined aqueous layers were madebasic by the addition of solid NaHCO₃ and were extracted twice withEtOAc. The organic phases were combined, dried over MgSO₄ andconcentrated in vacuo to give 534 mg (65%) of compound 497A as a lightbrown solid. HPLC: 96% at 0.55 min (retention time) (YMC S5 ODS column,4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 mincontaining 0.2%H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 165.0 [M+H]⁺.

B.(3aα,4β,5β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(7-methyl-6-benzothiazolyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione(497B)

6-Amino-7-methylbenzothiazole (29 mg, 0.18 mmol), MgSO₄ (54 mg, 0.45mmol), triethylamine (125 μL, 0.897 mmol) and compound 20A (52 mg, 0.26mmol) were taken up in 0.18 mL of DME and placed in a sealed tube. Thesealed tube was heated at 135° C. for 14 h. The cooled reaction mixturewas filtered through a short pad of Celite eluting with EtOAc and thesolvent was removed in vacuo. The residue was purified by reverse phasepreparative HPLC (YMC S5 ODS column, 20×100 mm, eluting with 30-100%aqueous methanol over 10 mincontaining 0.1% TFA, 20 mL/min, monitoringat 220 nm). Concentration of the desired fractions afforded a residuewhich was partitioned between CH₂Cl₂ (10 mL) and sat. NaHCO₃ solution(10 mL). The aqueous layer was extracted once with CH₂Cl₂ and thecombined organic phases were dried over Na₂SO₄ and concentrated in vacuoto give 42 mg (68%) of compound 497B as a tan solid. HPLC: 2.36 min &2.55 min (atropisomers, retention time) (YMC S5 ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 343.3[M+H]⁺.

EXAMPLE 498(3aα,4β,5β,7β,7aα)-5-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(498i) &(3aα,4β,5β,7β,7aα)-5-[Octahydro-5-hydroxy-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile(498ii)

Compound 464E (0.500 g, 1.02 mmol) was dissolved in THF (5.00 mL) andcooled to 0° C. BH₃.DMS (0.193 mL, 2.04 mmol) was then added slowlyfollowed by warming to 25° C. After 1 h, the reaction was cooled to 0°C. and pH 7 phosphate buffer (15.0 mL) was added resulting in theevolution of gas. EtOH (7.0 mL) and hydrogen peroxide (30%, 1.5 mL) werethen added and the reaction was warmed to 25° C. over 2 h. After 3 h,the mixture was extracted with methylene chloride (3×50 mL). Thecombined organic layers were washed once with brine and dried overanhydrous sodium sulfate. The product was complexed to boron afterworkup. All attempts to break up this complex failed to give the freeproduct. The crude material was taken on to the next step withoutfurther purification.

The crude reaction mixture was dissolved in 2% conc. HCl/MeOH (5.0 mL)at rt. After 1 h, the volatiles were removed in vacuo and the resultingresidue was dissolved in methylene chloride and washed once with sat.aq. sodium bicarbonate and dried over anhydrous sodium sulfate. Solventremoval in vacuo gave the crude mixture of compounds 498i and 498ii as ayellow solid. The mixture of compounds was separated by reverse phasepreparative HPLC: Compound 498i: 17.994 min (retention time) & compound498ii: 19.767 min (retention time) (YMC S5 ODS column, 30×250 mm, 25mL/min, 10-90% aqueous methanol over 35 mincontaining 0.1% TFA,monitoring at 220 nm). Solvent removal in vacuo gave 0.012 g (3%) ofcompound 498i as a white solid and 0.009 g (2%) of compound 498ii as awhite solid. Compound 498i: HPLC: 85% at 1.843 min (retention time) (YMCS5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 394.21 [M+H]⁺. Compound 498ii: HPLC: 98% at 1.650 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 394.21 [M+H]⁺.

EXAMPLE 499[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-4-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(499i) &[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[1(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-4-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(499ii)

The racemic compound 434C was separated into its individual antipodes bynormal phase preparative chiral HPLC using a Chiracel AD column (5 cm×50cm), eluting with 8% EtOH in hexane at 50 mL/min to give the fastereluting compound 499i (Chiral HPLC: 6.74 min; CHIRALCEL AD 4.6×250 mmcolumn; isocratic elution with 10% EtOH in hexane at 2 mL/min) and theslower eluting compound 499ii (Chiral HPLC: 9.99 min; CHIRALCEL AD4.6×250 mm column; isocratic elution with 10% EtOH in hexane at 2mL/min). For either compound 499i or 499ii: HPLC: 100% at 3.96 min(retention time) (YMC CombiSreen ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4mL/min, monitoring at 220 nm). MS (ES): m/z 521.25 [M+H]⁺. The absolutestereochemistry for compounds 499i & 499ii was not established. Forsimplicity in nomenclature, compound 499i is designated herein as havingan “R” configuration and compound 499ii as having an “S” configuration.Enantiomerically pure products derived from compound 499i are designatedherein as having a “R” configuration and enantiomerically pure productsderived from compound 499ii are designated herein as having an “S”configuration.

EXAMPLE 500[3aR-(3aα,4β,5β,7β,7aα)]-4-[4-Ethyloctahydro-5-hydroxy-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(500i) &[3aS-(3aα,4β,5β,7β,7aα)]-4-[4-Ethyloctahydro-5-hydroxy-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(500ii)

Compound 499i (24.0 mg, 0.0461 mmol) was dissolved in 2% conc. HCl/EtOH(0.8 mL) and the mixture was stirred at rt for 20 min. Cold sat. NaHCO₃was added to the mixture until the solution reached pH 8, then extractedwith EtOAc. The organic layers were combined, washed with brine anddried over anhydrous sodium sulfate. Concentration in vacuo gave 14.7 mg(78%) of compound 500i as a white solid which did not require furtherpurification. HPLC: 95% at 2.40 min (retention time) (YMC S5 ODS 4.6×50mm, 10%-90% aqueous methanol over 4 min gradient with 0.2% H₃PO₄,monitoring at 220 nm).

Compound 499ii (18.0 mg, 0.0346 mmol) was dissolved in 2% conc. HCl/EtOH(0.6 mL) and the mixture was stirred at rt for 20 min. Cold sat. NaHCO₃was added to the mixture until the solution reached pH 8, then extractedwith EtOAc. The organic layers were combined, washed with brine anddried over anhydrous sodium sulfate. Concentration in vacuo gave 14.1 mg(99%) of compound 500ii as a white solid which did not require furtherpurification. HPLC: 95% at 2.40 min (retention time) (YMC S5 ODS 4.6×50mm, 10%-90% aqueous methanol over 4 min gradient with 0.2% H₃PO₄,monitoring at 220 nm).

EXAMPLE 501[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-1,3-dioxo-7-propyl-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(501D)

A. 2-(5-Propyl-furan-2-yl)-ethanol (501A)

To a solution of 2-propylfuran (3.00 g, 31.2 mmol) in THF (31 mL) at−78° C. was added n-BuLi (15.0 mL, 2.5 M, 37.4 mmol) dropwise over 10min. The reaction was warmed to rt and stirred for 3.5 h. After coolingto 0° C., ethylene oxide (2.33 mL, 46.8 mmol) was added, the reactionwas warmed to rt and stirring was continued for 19 h. The reaction wasthen cooled to 0° C. and quenched with sat. NH₄Cl (20 mL), followed byextraction with Et₂O (2×50 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated to give 4.38 g(91%) of compound 501A as a bright orange oil. This material was usedwithout further purification. HPLC: 94% at 2.91 min (retention time)(YMC Combiscreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueousmethanol containing 0.2% phosphoric acid over 4 min, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 137.13 [M−H₂O+H]⁺.

B.(3aα,4β,7β,7aα)-4-[1,3,3a,4,7,7a-Hexahydro-4-(2-hydroxyethyl)-1,3-dioxo-7-propyl-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(501B)

A suspension of 2-(5-propyl-furan-2-yl)-ethanol (2.50 g, 16.2 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (4.02 g,16.2 mmol) in benzene (16 mL) was warmed to 60° C. After 3 h, thereaction was concentrated in vacuo to give a brown foam. Methanol (17mL) was added and the mixture was sonicated to give a fine beige solidwith a brown supernatant. Filtration gave 1.75 g (27%) of compound 501Bas an off-white solid. This material was used without furtherpurification. HPLC: 85% at 3.02 min & 3.14 min (atropisomers, retentiontime) (YMC Combiscreen ODS-A column, 4.6×50 mm, eluting with 10-90%aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 403.31 [M+H]⁺.

C.[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-(2-hydroxyethyl)-1,3-dioxo-7-propyl-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(501Ci) &[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-(2-hydroxyethyl)-1,3-dioxo-7-propyl-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(50Cii)

To a suspension of compound 501B (1.60 g, 3.97 mmol) in ethyl acetate(79.5 mL) was added 10% Pd/C (0.422 g, 0.397 mmol). Hydrogen gas wasbubbled through the reaction for several minutes and the reaction wasallowed to stir under a hydrogen atmosphere for 3 h. The reaction wasfiltered through Celite and the filtrate was concentrated in vacuo togive a white solid (1.74 g). The crude material was dissolved in minimumamount of methylene chloride and loaded on a 120 g silica gel ISCOcartridge. Elution with a step gradient of 0 to 100% ethylacetate/hexane gave 1.06 g (66%) of the racemic mixture of compounds501Ci & 501Cii as a white foam. A 500 mg portion of the racemic mixturewas separated by normal phase preparative chiral HPLC (Chiralpak AD;5×50 cm column; isocratic elution with 13% MeOH/EtOH (1:1) in heptane at50 mL/min, monitoring at 220 nm) to give 245 mg of the faster elutingenantiomer, compound 501Ci and 245 mg of the slower eluting enantiomer,compound 501Cii, both as a white foams. Compound 501Ci: Normal phasepreparative chiral HPLC: 28.0 min (retention time), >95% ee (ChiralpakAD 4.6×250 mm column, eluting with 12% MeOH/EtOH (1:1) in heptane at 1.0mL/min). HPLC: 99% at 3.04 & 3.17 min (atropisomers, retention time)(YMC Combiscreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoringat 220 nm). HRMS m/z Calc'd for C₂₄H₂₃N₂O₄ [M−H]⁻: 403.1658. Found403.1644. Compound 501Cii: Chiral HPLC: 65.7 min (retention time), >95%ee (Chiral HPLC: 65.7 min; >95% ee; Chiralpak AD 4.6×250 mm column;eluting with 12% MeOH/EtOH (1:1) in heptane at 1.0 mL/min). HPLC: 98% at3.02 & 3.15 min (atropisomers, retention time) (YMC Combiscreen ODS-Acolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). Theabsolute stereochemistry for compounds 501Ci & 501Cii was notestablished. For simplicity in nomenclature, compound 500Ci isdesignated herein as having an “R” configuration and compound 501Cii ashaving an “S” configuration. Enantiomerically pure products derived fromcompound 501Clare designated herein as having a “R” configuration andenantiomerically pure products derived from compound 500Cii aredesignated herein as having an “S” configuration.

D.[3aR-(3aα4β,7β,7aα)]-4-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-1,3-dioxo-7-propyl-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(501D)

To a solution of DBAD (17.1 mg, 0.0741 mmol) in THF (0.5 mL) was addedPPh₃ (19.4 mg, 0.0741 mmol). After 10 min, 5-chloro-2-pyridinol (9.6 mg,0.074 mmol) was added. After 5 min, compound 501Ci (20.0 mg, 0.0494mmol) was added. After 1 h, DBAD (17.1 mg, 0.0741 mmol), PPh₃ (19.4 mg,0.0741 mmol), and 5-chloro-2-pyridinol (9.6 mg, 0.074 mmol) were added.After 3 h, the solvent was removed in vacuo to give a yellow residue.Preparative reverse phase HPLC (YMC ODS column, 20×100 mm, eluting with40-100% aqueous methanol containing 0.1% TFA over 30 min, 25 mL/min,monitoring 220 nm) gave 9.5 mg (37%) of the trifluoracetic acid salt ofcompound 501D as a clear, colorless residue. HPLC: 99% at 7.88 min &8.11 min (atropisomers, retention time) (Zorbax SB C18 4.6×75 mm,eluting with 10-90% aqueous methanol over containing 0.2% phosphoricacid over 8 min, 2.5 mL/min, monitoring at 220 nm). HRMS m/z Calc'd forC₂₉H₂₇N₃O₄Cl [M+H]⁺: 516.1690. Found 516.1676.

EXAMPLE 502[3aR-(3aα,4β,7β,7aα)]-4-[4-Butyl-7-[2-[(5-chloro-2-pyridinyl)oxy]ethyl]octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(502D)

A. 2-(5-Butyl-furan-2-yl)-ethanol (502A)

To a solution of 2-butylfuran (3.00 g, 24.2 mmol) in THF (24 mL) at −78°C. was added n-BuLi (11.6 mL, 2.5 M, 29.0 mmol) dropwise over 10 min.The reaction was warmed to rt and stirred for 3.5 h. After cooling to 0°C., ethylene oxide (1.81 mL, 36.2 mmol) was added, the reaction waswarmed to rt and stirring was continued for 19 h. The reaction was thencooled to 0° C. and quenched with sat. NH₄Cl (20 mL), followed byextraction with diethyl ether (2×50 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo to give 4.07 g (100%) compound 502A as a bright orange oil. Thismaterial was used without further purification. HPLC: 96% at 3.23 min(retention time) (YMC Combiscreen ODS-A column, 4.6×50 mm, eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4mL/min, monitoring at 220 mm). MS (ES): m/z 169.22 [M+H]⁺.

B.(3aα,4β,7β,7aα)-4-[4-Butyl-1,3,3a,4,7,7a-hexahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(502B)

A suspension of compound 502A (2.50 g, 14.9 mmol) and4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenecarbonitrile (3.70 g,14.9 mmol) in benzene (15 mL) was warmed to 60° C. After 3 h, thereaction was concentrated in vacuo to give a brown foam. Methanol (17mL) was added and the mixture was sonicated to give a fine beige solidwith an orange-brown supernatant. Filtration of the precipitate gave2.64 g (44%) of compound 502B as an off-white solid. This material wasused without further purification. HPLC: 95% at 3.25 min & 3.35 min(atropisomers, retention time) (YMC Combiscreen ODS-A column, 4.6×50 mm,eluting with 10-90% aqueous methanol containing 0.2% phosphoric acidover 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 417.29 [M+H]⁺.

C.[3aR-(3aα,4β,7β,7aα)]-4-[4-Butyloctahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(502Ci) &[3aS-(3aα,4β,7β,7aα)]-4-[4-Butyloctahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(502Cii)

To a suspension of compound 502C (1.47 g, 3.52 mmol) in ethyl acetate(70 mL) was added 10% Pd/C (0.375 g, 0.352 mmol). Hydrogen was bubbledthrough the reaction for several minutes and the reaction was allowed tostir under a hydrogen atmosphere for 3 h. The reaction was filteredthrough Celite®, rinsing with ethyl acetate (2×70 mL). The filtrate wasconcentrated in vacuo to give a white foam (1.50 g). The crude materialwas dissolved in a minimum amount of methylene chloride and loaded on a120 g silica gel ISCO cartridge. Elution with a step gradient of 0 to100% ethyl acetate/hexane gave 1.05 g (74%) a racemic mixture ofcompounds 502Ci & 502Cii as a white foam. A 438 mg portion of racemicmixture of compounds 502Ci & 502ii was separated by normal phasepreparative chiral HPLC (Chirapak AD column, 5×50 cm, isocratic elutionwith 12% MeOH/EtOH (1:1) in heptane at 50 mL/min, monitoring at 220 nm)to yield 178 mg of the faster eluting enantiomer, compound 502Ci as awhite foam and 132 mg of the slower eluting enantiomer, compound 502Cii,as a clear, viscous oil. Compound 502Ci: Chiral HPLC: 25.5 min(retention time), >95% ee (Chiral HPLC: Chiralpak AD 4.6×250 mm column,eluting with 12% MeOH/EtOH (1:1) in heptane at 1.0 mL/min) and HPLC: 99%at 6.50 min & 6.71 min (atropisomers, retention time) (YMC CombiscreenODS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol containing0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm) HRMSm/z Calc'd for C₂₅H₂₅N₂O₄ [M−H]⁻: 417.1814. Found 417.1800. Compound502Cii: HPLC: 55.6 min (retention time), >95% ee (Chiral HPLC: ChiralpakAD 4.6×250 mm column; eluting with 12% MeOH/EtOH (1:1) in heptane at 1.0mL/min). HPLC: 99% at 3.26 min & 3.38 min (atropisomers, retention time)(YMC Combiscreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueousmethanol containing 0.2% phosphoric acid over 4 min, 4 mL/min,monitoring at 220 nm). The absolute stereochemistry for compounds 502Ci& 502Cii was not established. For simplicity in nomenclature, compound502Ci is designated herein as having an “R” configuration and compound502Cii as having an “S” configuration. Enantiomerically pure productsderived from compound 502Clare designated herein as having a “R”configuration and enantiomerically pure products derived from compound502Cii are designated herein as having an “S” configuration.

D.[3aR-(3aα,4β,7β,7aα)]-4-[4-Butyl-7-[2-[(5-chloro-2-pyridinyl)oxy]ethyl]octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(502D)

To a solution of compound 502Ci (20.0 mg, 0.0478 mmol), PPh₃ (37.6 mg,0.143 mmol) and 5-chloro-2-pyridinol (18.6 mg, 0.143 mmol) in THF (0.5mL) was added DBAD (33.0 mg, 0.143 mmol). The resulting solution wasstirred at rt for 15.5 h. The solvent was removed in vacuo to give ayellow residue. Preparative HPLC (Shimadzu VP ODS column, 20×250 mm,eluting with 40-100% aqueous methanol containing 0.1% TFA over 30 minand 100% for 25 min, 25 mL/min, monitoring at 220 nm) gave 9.4 mg (37%)of the trifluoracetic acid salt of compound 502D as a clear, colorlessresidue. HPLC: 99% at 8.14 min & 8.36 min (atropisomers, retention time)(Zorbax SB C18 column, 4.6×75 mm, eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over 8 min, 2.5 mL/min, monitoring at220 nm). HRMS m/z Calc'd for C₃₀H₂₉N₃O₄Cl [M+H]⁺: 530.1847. Found530.1855.

EXAMPLE 503(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[4-(5-oxazolyl)-1-naphthalenyl]-4,7epoxy-1H-isoindole-1,3(2H)-dione (503E)

A. (4-Cyano-naphthalen-1-yl)-carbamic acid tert-butyl ester (503A)

To a solution of 4-amino-1-naphthalenecarbonitrile (9.67 g, 57.5 mmol)in THF (100 mL) at rt was added, over 10 min, sodiumhexamethyldisilazane (1.0 M in THF, 133 mL, 133 mmol). After stirringfor 15 min, a solution of di-t-butyldicarbonate (15.1 g, 69.0 mmol) inTHF (20 mL) was added. After stirring for 18 h at rt, the reactionmixture was partitioned between Et₂O (400 mL) and saturated potassiumbisulfate solution (200 mL). The organic layer was washed with saturatedpotassium bisulfate solution (200 mL), saturated sodium bicarbonatesolution (200 mL) and brine (100 mL). Drying over anhydrous magnesiumsulfate, treatment with decolorizing carbon and concentration in vacuo,afforded a residue that was partially purified by flash chromatographyon silica gel eluting with 20% ethyl acetate in hexane. The partiallypurified material was crystallized from ethyl acetate/hexane to give5.26 g of compound 503A as a colorless crystals. The mother liquor wasconcentrated and crystallized from ethyl acetate/hexane to give anadditional 2.8 g of compound 503A to yield a total of 8.06 g (52%) ofcompound 503A. ¹HNMR (400 MHz, DMSO-d⁶): δ 9.81(s, 1H), 8.36 (d, 1H,J=8.5 Hz), 8.11 (m, 2H), 7.92 (d, 1H, J=8 Hz), 7.78 (m, 1H), 7.67 (m,1H), 1.53 (s, 9H).

B. (4-Formyl-naphthalen-1-yl)-carbamic acid tert-butyl ester (503B)

A mixture of compound 503A (4.02 g, 15.0 mmol), Raney nickel (1.5 g),sodium hypophosphite (9.00 g, 86.5 mmol), pyridine (50 mL), water (25mL) and acetic acid (25 mL) was stirred at 45° C. for 5 h. The mixturewas filtered through celite and the filter cake was rinsed with warmethanol (100 mL). After adding water (600 mL) to the filtrate andallowing it to stand for 1 h, the resulting precipitate was filtered andrinsed with water. Drying in vacuo afforded 3.38 g of a white solidwhich was a 3:1 mixture of compounds 503B & 503A. The material was usedin the next step without further purification. ¹HNMR (400 MHz, DMSO-d⁶):δ 10.28 (s, 1H), 9.77 (s, 1H), 9.27 (d, 1H, J=8.5 Hz), 8.31 (m, 1H),8.13 (m, 1H), 8.00 (d, 1H, J=8 Hz), 7.80 (m, 1H), 7.70 (m, 1H), 1.54 (s,9H).

C. (4-Oxazol-5-yl-naphthalen-1-yl)-carbamic acid tert-butyl ester (503C)

The above mixture of compounds 503A & 503B (3.37 g, 10.0 mmol; correctedfor presence of compound 503A), toluene-sulfonylisocyanide (2.15 g, 11.0mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 50 mL of methanolwas refluxed for 4 h. The reaction mixture was partitioned between water(200 mL) and chloroform (200 mL). After extracting the aqueous layerwith chloroform (100 mL), the combined organic layers were dried overmagnesium sulfate and concentrated in vacuo. The crude residue waspurified by flash chromatography on silica gel eluting with a gradientof 10-40% ethyl acetate in hexane to give 1.35 g (44%) of compound 503Cas a white solid. ¹HNMR (400 MHz, DMSO-d⁶): δ 9.45 (s, 1H), 8.57 (s,1H), 8.20 (m, 2H), 7.76 (m, 2H), 7.64 (s, 1H), 7.62 (m, 2H), 1.51 (s,9H).

D. 4-Oxazol-5-yl-naphthalen-1-ylamine (503D)

Compound 503C (1.34 g, 4.3 mmol) was dissolved in trifluoroacetic acid(10 mL) and the resulting mixture was allowed to stand for 1 h at roomtemperature. After removing the volatiles in vacuo, the residue wasco-evaporated from ethyl acetate/heptane (2×50 mL) to remove traces oftrifluoroacetic acid. After partitioning the residue between ethylacetate (100 mL) and 1N NaOH (75 mL), the organic layer was washed withbrine (50 mL), dried over magnesium sulfate and concentrated in vacuo toafford 900 mg (99%) of compound 503D as a yellow crystalline solid. HPLCconditions: 95% at 0.92 min (retention time) (Phenomenex 5 micronODScolumn, 4.6×30 mm, 10%-90% aqueous methanol over 2 min gradient with0.1% TFA, monitoring at 254 nm.). MS (ES): m/z 211.22 [M+H]⁺.

E.(3aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-[4-(5-oxazolyl)-1-naphthalenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione(503E)

A mixture of compound 503D (42 mg, 0.020 mmol) and 20A (78 mg, 0.40mmol) in acetic acid (1.0 mL) was refluxed for 18 h. The reactionmixture was cooled to rt, concentrated in vacuo and the residue waspartitioned between ethyl acetate (30 mL) and saturated sodiumbicarbonate solution (30 mL). The organic layer was isolated, dried overmagnesium sulfate and concentrated in vacuo. Purification by flashchromatography on a 2.5×15 cm silica gel column, using a gradient of40-60% ethyl acetate in hexane gave 28 mg (37%) of compound 503E as awhite powder. HPLC: 99% at 1.46 min & 1.36 min (atropisomers, retentiontime) (Phenomenex 5 micron ODS 4.6×30 mm, 10%-90% aqueous methanol over2 min gradient with 0.1% TFA, monitoring at 254 nm.). MS (ES): m/z389.10 [M+H]⁺.

EXAMPLE 504[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(4-Cyanophenoxy)ethyl]-4-ethyloctahydro-5-methoxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(504C)

A.[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-4-ethyloctahydro-5-methoxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(504A)

To a solution of compound 499ii (0.235 g, 0.451 mmol) in CH₃CN (6 mL)was added silver oxide (0.523 g, 2.26 mmol) and iodomethane (0.56 mL,9.0 mmol, stirred over K₂CO₃ before addition). The resulting suspensionwas placed in a preheated oil bath (80° C.). After 24 h, the reactionwas cooled to rt, diluted with CH₃CN (20 mL), filtered through a plug ofCelite, and concentrated in vacuo to give a brown gum. Purification byflash chromatography on silica gel eluting with 30% ethylacetate/hexanes gave 0.156 g (65%) of compound 504A as a white solid.HPLC: 95% at 4.17 min & 4.25 min (atropisomers, retention time) (YMCCombiSreen ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220nm). MS (ES): m/z 521.25 [M+H]⁺.

B.(3aα,4β,5β,7β,7aα)-4-[4-Ethyloctahydro-7-(2-hydroxyethyl)-5-methoxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(504B)

To a solution of compound 504A (0.156 g, 0.292 mmol) in ethanol (6 mL)was added 1N HCl (0.44 mL, 0.44 mmol). After 20 min, the reaction wascooled to 0° C. and quenched with sat. aq. NaHCO₃ (2 mL) to give a whitesuspension. Added H₂O until the solid dissolved. The mixture wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered, and concentratedin vacuo to give a white solid. Purification by flash chromatography onsilica gel eluting with 5% MeOH/CH₂Cl₂ gave 120 mg (99%) of compound504A as a white solid. HPLC: 98% at 5.17 and 5.44 min (atropisomers,retention time) (YMC CombiSreen ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over 8 min, 2.5mL/min, monitoring at 220 nm). HRMS m/z Calc'd for C₂₄H₂₄N₂O₅ [M−H]⁺:419.1607. Found 419.1611.

C.[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(4-Cyanophenoxy)ethyl]-4-ethyloctahydro-5-methoxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(504C)

To a solution of compound 504B (20 mg, 0.048 mmol) in anhydrous THF (0.5mL) was added PPh₃ (37.0 mg, 0.143 mmol), para-cyanophenol (17.0 mg,0.143 mmol) and DBAD (32.0 mg, 0.143 mmol). After 30 min, the solutionwas concentrated to give a brown gum. Purification by reverse phasepreparative HPLC (YMC S5 ODS column, 20×250 mm, eluting with 10-90%aqueous methanol containing 0.2% phosphoric acid over 35 min, 20 mL/min,monitoring at 220 nm) gave 16 mg (64%) of compound 504C as a clear,colorless oil. HPLC 98% at 6.84 and 7.10 min (atropisomers, retentiontime) (Zorbax SB C18 column, 4.6×75 mm, eluting with 10-90% aqueousmethanol containing 0.2% phosphoric acid over 8 min, 2.5 mL/min,monitoring at 220 nm). HRMS m/z Calc'd for C₃₁H₂₇N₃O₅ [M+NH₄]⁺:539.2295. Found 539.2302.

EXAMPLE 505(3aα,4β,5β,7β,7aα)-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-4-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(505Bi) &(3aα,4β,5β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-7-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(505Bii)

A.(1aα,2β,2aα,5aα,6β,7aα)-4-[2-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-6-ethyloctahydro-3,5-dioxo-2,6-epoxy-4H-oxireno[f]isoindol-4-yl]-1-naphthalenecarbonitrile(505A)

To a solution of compound 434B (1.01 g, 2.01 mmol) in methylene chloride(20 mL) was added 60% m-CPBA (0.863 g, 3.00 mmol). After 48 h, thereaction was diluted with methylene chloride (50 mL) and washed withsat. Na₂SO₃ (20 mL) and sat. NaHCO₃ (20 mL). The combined aqueous layerswere extracted with CH₂Cl₂ (20 mL). The combined organic layers werewashed with brine (30 mL), dried over Na₂SO₄, filtered, and concentratedin vacuo to give 1.01 g (97%) of compound 505A as a yellow solid. Thismaterial used without further purification. HPLC: 95% at 4.22 min(retention time) (Phenominex Luna C18 column, 4.6×50 mm, eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4mL/min, monitoring at 220 nm). HRMS m/z Calc'd for C₂₉H₃₄N₂O₅Si [M−H]⁺:517.2159. Found 517.2163.

B.(3aα,4β,5β,7β,7aα)-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-4-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(505Bi) &(3aα,4β,5β,7β,7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-7-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(505Bii)

To a red solution of titanocene dichloride (0.500 g, 2.00 mmol) inanhydrous THF (4.0 mL) was added zinc dust (0.392 g, 6.00 mmol). Theresulting suspension was vigorously stirred for 1 h under an argonatmosphere to give a green suspension. Excess zinc was removed byfiltration through a 0.45 μm microfilter to give a green solution ofdicyclopentadienyl titanium (III) chloride. To a solution of compound505A (0.207 g, 0.399 mmol) and 1,4-cyclohexadiene (0.380 mL, 4.02 mmol)in anhydrous THF (1 mL) was added dropwise a 0.5 M solution of the abovedescribed dicyclopentadienyl titanium (III) chloride (0.9 mL, 0.45mmol). After 1 h, an additional aliquot of the 0.5 M solution ofdicyclopentadienyl titanium (III) chloride (0.9 mL, 0.45 mmol) was addedand stirring was continued for 1 h. The reaction was then quenched withwater (2 mL) and diluted with ethyl acetate (10 mL). The layers wereseparated and the organic layer was washed with brine (5 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo to give a yellow gum. Thecrude material was dissolved in a minimum amount of methylene chlorideand loaded on a 35 g silica gel ISCO column. Gradient elution with 0-80%ethyl acetate in hexane gave 0.043 g (21%) of compound 505Bi as a whitesolid and 0.023 g (11%) of compound 505Bii as a white solid. Compound505Bi: HPLC: 3.92 min (retention time) (YMC CombiSreen ODS-A column,4.6×50 mm, eluting with 10-90% aqueous methanol containing 0.2%phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES):m/z 521.36 [M+H]⁺. Compound 505Bii: HPLC: 91% at 3.97 min (retentiontime) (YMC CombiScreen ODS-A column, 4.6×50 mm, eluting with 10-90%aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 521.34 [M+H]⁺.

EXAMPLE 5064-[[3aS-(3aα,4β,5β,7β,7aα)]-5-(α-D-Glucopyranosyloxy)octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(506B)

A.[3aS-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-4,7-dimethyl-1,3-dioxo-5-[[2,3,4,6-tetrakis-O-(phenylmethyl)-α-D-glucopyranosyl]oxy]-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(506A)

2,3,4,6-Tetra-O-benzyl-α-D-glucopyranosyl bromide was made according tothe procedure by Spohr et al. Can. J. Chem. 71, 1928-42 (1993). Oxalylbromide (0.48 mL, 0.95 mmol, 2 M in CH₂Cl₂) was added dropwise to asolution of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (412 mg, 0.763 mmol)in CH₂Cl₂ (5 mL) and DMF (0.28 mL) at rt under Ar. The reaction mixturewas stirred for 20 min, poured onto a mixture of ice and H₂O (1:1, 30mL) and diluted with CH₂Cl₂ (30 mL). The layers were separated and theorganic layer was washed with cold H₂O (2×30 mL) and brine (1×30 mL) anddried over MgSO₄. Concentration in vacuo gave the desired bromide as abrown oil. This oil was taken up in CH₂Cl₂ (2 mL) and DMF (1 mL).Compound 471Dii (100 mg, 0.763 mmol), tetrabutylammonium bromide (111mg, 0.526 mmol) and 4 Å sieves (600 mg) were added to this solution andthe reaction was stirred under Ar for 4 d. The reaction was quenchedwith MeOH (2 mL), stirred for 0.5 h, diluted with CH₂Cl₂ (10 mL) andthen filtered through a medium porosity fritted funnel, rinsing withCH₂Cl₂ (5 mL). The solvent was removed in vacuo and the resultingresidue was dissolved in CH₂Cl₂ (25 mL). The organic solution was washedwith sat. aq. NaHCO₃ (1×20 mL) and H₂O (1×20 mL) and dried over MgSO₄.Purification by flash chromatography on SiO₂ eluting with 50%EtOAc/hexanes gave 79 mg (33%) of 506A as a white solid. HPLC: 99% at4.56 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 902 [M+H]⁺.

B.4-[[3aS-(3aα,4β,5β,7β,7aα)]-5-(α-D-Glucopyranosyloxy)octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(506B)

Palladium hydroxide (62 mg, 20 wt. % Pd (dry basis) on carbon, wet) wasadded to a solution of 506A (65 mg, 0.07 mmol) in EtOAc (2 mL) and themixture was stirred under a hydrogen atmosphere introduced via aballoon. After 5 h, the reaction was complete as was evident by HPLC, sothe mixture was filtered through a medium porosity fritted funnelrinsing with MeOH (2 mL) and concentrated in vacuo. The resultingresidue was dissolved in MeOH (2 mL) and filtered through a GelmanAcrodisc CR 13 mm syringe filter with a 0.45 μM PTFE membrane.Concentration yielded 38 mg of 506B as a white solid. HPLC: 90% at 2.16min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 mm). MS (ES): m/z 543.20 [M+H]⁺. A 10 mg portion wasrecrystallized from MeOH:H₂O to give crystals suitable for X-ray crystaldiffraction studies to elucidate the exact stereochemistry of compound506B as referenced to the known fixed stereochemistry of the D-glucosideappendage.

EXAMPLE 507(3aα,4β,7β,7aα)-4-(1,3,3a,4,7,7a-Hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(507)

To 25 g (94.2 mmol) of compound 471A was added neat 2,5-dimethylfuran(30 mL, 280 mmol), and the resulting slurry was heated to 60° C. for 1to 3 h with mechanical agitation. The resulting slurry was cooled to0-5° C., and diluted with cold toluene (25 mL, 0-10° C.). The coldslurry was filtered under vacuum. The flask and filter cake were washedwith cold toluene (2×25 mL), and the cake was deliquored with housevacuum. The precipitate was dried in vacuo to yield 31.3 g (91.6%) of acompound 507 as a tan solid. HPLC: 99.6%, 19.43 min (retention time)(Column: Zorbax™ SB-C18, 4.6×15 cm; Mobile Phase: 40% CH₃CN/60% H₂Ow/0.1% v/v TFA, isocratic; Flow Rate: 1 mL/min; Detection: λ_(max) 210nm; Temperature: 30° C.; Injection Volume: 5 μL).

EXAMPLE 508(3aα,4β,5β,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(508)

To THF (275 mL) that had been cooled to −3° C. was added compound 507(55.0 g, 152 mmol), which resulted in a slurry. To the slurry was addedborane methylsulfide (14.4 mL, 152 mmol), at a rate such that thetemperature did not exceed 0° C. The reaction mixture was slowly warmedto 20° C. over 2.5 h. The temperature of the reaction mixture was thenreturned to 0° C., where upon phosphate buffer (1056 mL, pH 7) wascarefully added at a rate to control the hydrogen gas evolution andmaintain a temperature ≦20° C. The resulting suspension was dissolved byadding ethanol (528 mL, 190 proof). At 15° C., hydrogen peroxide (55 mL,30 wt %) was added at a rate to maintain the temperature <20° C. Thehomogeneous solution was left stirring for 12 h at 20° C. and pH 7.8,whereby crystallization occurred. The resulting slurry was collected byfiltration and washed with water (4×100 mL) and methyl-tert-butyl ether(2×100 mL). Drying in vacuo afforded 37.3 g (64.6%) of compound 508. Theaqueous mother liquor was extracted with ethyl acetate (3×500 mL). Thecombined rich organics were washed with 10 wt % aqueous sodium sulfite(1×100 mL), and 25 wt % aqueous sodium chloride (1×100 mL). The organicswere dried over sodium sulfate, filtered, and concentrated to recover8.9 g (15.4%) of compound 508, and a third 11.5 g (20%) fraction ofcompound 508 was recovered from the methyl-tert-butyl ether cake wash.The above three solid samples of crude material were separatelyrecrystallized from 190 proof ethanol (1 g/10 mL) to afford a total of35.6 g (61.7%) of compound 508 having a purity level of 98.7% asdetermined by HPLC analysis (conditions as below). A second crop ofcompound 508 was isolated from the mother liquor to afford 9.3 g (16.1%)of solid having a purity level of 98.4% as determined by HPLC analysis.The remaining mother liquor was purified by silica gel chromatographyusing 200 g of SiO₂ and eluting with 4 L of 50V % ethyl acetate and 50 V% heptane to yield 5.6 g (9.7%) of compound 508, having a purity levelof 94.0% as determined by HPLC analysis. HPLC conditions: 9.74 minuteretention time on a YMC S5 ODS-AQ column (4.6×150 mm) using a gradientelution from 100% solvent A to 100% solvent B over 15 minutes at 1.0mL/min. Solvent A=95 V % water (0.01 M NH₄OAc); 5 V % acetonitrile.Solvent B=5 V % water (0.01 M NH₄OAc); 95 V % acetonitrile. Duelwavelength detector set at 210 and 245 nm. MS (ES): m/z 381.11 [M+H]⁺.

EXAMPLE 509(3aα,4β,5β,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(509)

Compound 471A (0.37 g, 1.4 mmol) and 2,5-dimethylfuran (0.73 mL, 6.9mmol) were combined to form a slurry which was heated to 60° C. for 1 h.The reaction mixture was cooled to −10° C. and THF (1.0 mL) was addedfollowed by the addition of borane tetrahydrofuran (2.1 mL, 1 M). Thereaction mixture was stirred for 30 minutes at 0° C. and 30 minutes at+10° C. To the reaction mixture was added acetone (3.0 mL), and theresulting mixture was warmed to 20° C. and maintained at 20° C. for 1 h.To this solution was added sodium bicarbonate (1.5 mL, pH 9, 8 wt %) andthe mixture was then cooled to 5° C. before adding hydrogen peroxide(0.3 mL, 30 wt %). Addition of hydrogen peroxide was exothermic bringingthe temperature to 20° C. A solution of sodium sulfite (4.0 mL, 10 wt %)was added at 20° C. resulting in an exotherm to 30° C. The biphasicmixture was allowed to stand at 25° C. for 12 h. After the phases wereseparated, the aqueous waste was back extracted twice with ethyl acetate(5 mL) and the combined organic layers were washed with water (2 mL)followed by sodium chloride (2 mL, 25 wt %). The organic layers wereconcentrated in vacuo to yield a yellow oil which rapidly crystallized.To the crude product was added 190 proof ethanol (5.0 mL) and themixture was heated to 60° C. to afford complete dissolution. Cooling to20° C. for 17 h resulted in crystallization. The crystal slurry wascollected by filtration, washed with heptane (5 mL), and dried at 60° C.under vacuum (30 in/Hg) to afford 0.23 g (44%) of compound 509 having93.1 HPLC Area %. HPLC conditions: 9.74 minute retention time on a YMCS5 ODS-AQ column (4.6×150 mm) using a gradient elution from 100% solventA to 100% solvent B over 15 minutes at 1.0 mL/min. Solvent A=95 V %water (0.01 M NH₄OAc); 5 V % acetonitrile. Solvent B=5 V % water (0.01 MNH₄OAc); 95 V % acetonitrile. Detector set at 245 nm. MS (ES): m/z381.11 [M+H]⁺.

EXAMPLE 510[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(510i) &[3aS-(3aα,4β,5β,7β,7aα)-4-[5-(Acetyloxy)octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(510ii)

Compound 509 (4 mg), vinyl acetate (0.1 mL) and toluene (2 mL) werecombined and 20 mg of each of the enzymes shown in Table 12 were added.The mixture was stirred with a magnetic stirring bar at rt in a 16×100mm capped tube for the time period listed in Table 12. Theenantioselective acetylation of the racemic mixture resulted in theformation of compound 510i and the acetylated compound 510ii. Theenantiomeric purity of compound 510i was determined by chiral HPLC(method below) and the results for each enzyme are as shown in Table 12.The resulting information was used to prepare a large scale batch ofcompounds 510i & 510ii as described below.

TABLE 12 Comp. Comp. Comp. Comp. Time 510i 510i 510i 510ii EnzymeSupplier Source H mg/mL % yield % ee mg/mL AK-20 Amano Pseudomonas 150.74 39 100 1.02 fluorescens AP-12 Amano Aspergillus niger 144 1.10 5855.4 0.74 PS-30 Amano Pseudomonas 15 0.46 24 100 1.24 cepacia AcylaseAmano Aspergillus 15 0.51 27 12.2 1.26 30000 Chirazyme BoehringerCandida rugosa 144 0.81 42 87.2 1.04 L3 Lipase type Sigma Candida rugosa144 0.74 39 100 1.06 VII

To a 500 mL jacketed flask were added Amano lipase AK20 from Pseudomonasfluorescens (25 g), compound 509 (25 g), methyl-isobutyl-ketone (475 mL)and vinyl acetate (25 mL). The flask was maintained at 25° C. with acirculating water bath and stirred with a magnetic stir bar. Theincubation was continued for 42 h, at which point the enantiomericexcess of compound 510i reached 100%. The solution was filtered throughWhatman 4 filter paper to remove enzyme and the filter cake was washedwith 50 mL methyl isobutyl ketone. The filtrate was concentrated invacuo and the resulting residue was dissolved in EtOAc (50 mL) followedby the addition of heptane (50 mL). This solution was loaded onto aPhenomenex cartridge column (silica 800 g) in a Biotage 75L system andthe column was eluted with 75% EtOAc/heptane at flow rate 110 mL/min.Fractions were collected (500 mL) which contained compound 510ii andthen the eluting solvent was changed to 100% EtOAc to elute off compound510i. The desired fractions were pooled and the solvent was removed invacuo to yield 11.0 g of compound 510i, (44%, 100% ee) and 12.10 g ofcompound 510ii (44%). Compound 510i was re-crystallized from 95% EtOH (5mL/g) in two crops to afford 9.61 g (38%) of compound 510i as a whitecrystalline solid. Compounds 510i: Chiral HPLC: 10.02 min (retentiontime) (CHIRALPAK AD 4.6×250 mm column; isocratic elution with 20%MeOH/EtOH (1:1) in heptane at 1 mL/min). HPLC: 99% at 2.45 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 381.11 [M+H]⁺.

EXAMPLE 511[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(511i) & Butanedioic acid,mono[3aS-(3aα,4β,5β,7β,7aα)]-[2-[4-cyano-3-(trifluoromethyl)phenyl]octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindol-5-yl]ester-(511ii)

A mixture of the racemic compound 509 (10 mg), succinic anhydride (100mg) and lipase AK-20 Amano (50 mg) in toluene or MTBE (5 mL) was stirredat rt for 20 hours. After 16 and 20 h, samples (0.1 mL) were taken outfrom each reaction mixture, evaporated, redissolved in acetonitrile (1mL) and analyzed by reversed phase HPLC (YMC Pro-pack ODS-A, 3μ, 15×0.6cm, acetonitrile:water 20:80 to 90:10 in 12 min) to determine the arearatio of products compound 511i (RT=8.8 min) and compound 511ii (RT=9.9min). A second sample (0.1 mL) of each reaction mixture was removed,evaporated and redissolved in 1 mL isopropyl alcohol-heptane (1:1) andanalyzed by Chiral HPLC (Chiralpak AD, 25×0.46 cm, 20° C.,heptane:ethanol 85:15, 0.5 mL/min, UV 210 nm) to determine the % ee ofcompound 511i (RT=32.2 min) and compound 471Dii (RT=34.8 min). After 20h, the reaction mixtures were filtered off to separate the insolublecomponents (enzyme, etc.). The filtrates were washed with 5% aqueousNaHCO₃ (3×1 volume) and water (3×1 volume), evaporated in vacuo andanalyzed by HPLC as described above. The results showed an average yieldof 48% (theoretical max yield is 50%) and 100% ee for compound 511i.Complete separation of compound 511ii was achieved via the abovedescribed NaHCO₃ extraction. Table 13 gives the details of each reactionas determined by the methods described above. Compound 511i: ChiralHPLC: 10.02 min; CHIRALPAK AD 4.6×250 mm column; isocratic elution with20% MeOH/EtOH (1:1) in heptane at 1 mL/min, 100% ee. HPLC: 99% at 2.45min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 381.11 [M+H]⁺.

TABLE 13 Comp. Comp. 511i 511ii Comp Comp Comp. Lipase Succinic 8.8 min9.9 min 511i 471Dii Comp. Solvent 509 AK-20 Anhydride Time Area Area32.2 min 34.8 min 511i Solvent Vol., ml mg mg mg Hr Ratio Ratio % % ee %Toluene 5 10 50 100 16 53% 47% 93.1% 6.9% 86.2% 20 54% 46% 96.0% 4.0%92.0% Toluene 100% 0% 96.1% 3.9% 92.2% Wash NaHCO3 MTBE 5 10 50 100 1649% 51% 100.0% 0.0% 100.0% 20 50% 50% 100.0% 0.0% 100.0% MTBE 100% 0%100.0% 0.0% 100.0% Wash NaHCO3

EXAMPLE 512[3aR-(3aα,4β,5β,7β,7aα)-4-[5-(Acetyloxy)octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(512i) &[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(512ii)

A series of 50 mL flasks were arranged and enzymes (see Table 14 forenzyme type and amounts) were weighed into each followed by the additionof phosphate buffer (BF45, 5 mL, 100 mM, pH 7). A solution of compound473 (5 mg) in DMSO (50 μL) was added to each flask. The flasks wereshaken at 200 rpm at 28° C. for 24 hours. After 24 hours, the reactionmixtures were extracted with EtOAc (10 mL). A portion of the EtOAcextract (1 mL) was evaporated, redissolved in acetonitrile (1 mL) andanalyzed by reversed phase HPLC (C-18, acetonitrile:water 20:80 to 90:10in 12 min) to determine the area ratio of compound 512i (RT=11.0 min)and compound 512ii, (RT=8.9 min). Another portion of EtOAc extract (4mL) was evaporated, redissolved in 1 mL isopropyl alcohol-heptane (1:1)and analyzed by chiral HPLC (Chiralpak AD, heptane:ethanol 85:15, 0.5mL/min) to determine the % ee of the compound 512ii (RT=34.8 min) andcompound 471Di (RT=32.2 min) in this system. Table 14 gives details foran array of different enzymes examined and the resulting yields and % eefor the desired products.

TABLE 14 Enz Amt Area Ratio by HPLC Exo-Alcohol Exo-Alcohol % ee ofEnzyme Supplier Source mg Comp. 512ii Comp. 512i Comp 471Di Comp. 511iiComp 512ii Lipase AP-12 Amano Aspergillus niger 5 18% 82% 18.8% 81.2%62.5% Lipase AP-12 Amano Aspergillus niger 25 50% 50% 41.0% 59.0% 17.9%Lipase PS Amano Pseudomonas cepacia 5 20% 80% 31.3% 68.7% 37.4% LipasePS Amano Pseudomonas cepacia 25 46% 54% 40.2% 59.8% 19.6% Acylase 150000Amano Aspergillus sp 5 30% 70% 52.0% 48.0% −3.9% Acylase 150001 AmanoAspergillus sp 25 71% 29% 50.4% 49.6% −0.8% Newlase F Amano Rhizopusniveus 50 3% 97% 31.3% 68.7% 37.5% Newlase F Amano Rhizopus niveus 1003% 97% 25.7% 74.3% 48.5% Acylase I Sigma Apergillus melleus 5 10% 90%9.7% 90.3% 80.6% Acylase I Sigma Apergillus melleus 25 38% 62% 10.9%89.1% 78.3% Esterase Sigma Porcine liver 5 76% 24% 36.0% 64.0% 27.9%

EXAMPLE 513[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(513i) &[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile& (513ii) &(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(513iii)

A series of microbial biotransformation reactions were set up togenerate compounds 513i, 513ii & 513iii. The details of the reactionsfor several microorganisms are shown in Table 15 and a general procedureis described below. One thawed vial of the microbe (1 mL culture) wasinoculated into sterile soybean-glucose media (10 mL) in a 50 mL flask.The microbes were grown by shaking at 200 rpm at 28° C. for 40 h. Asolution of compound 472 (10 mg in 100 μL DMSO) was added to each flaskand the flasks were shaken at 200 rpm at 28° C. At 24 and 48 h, 5 mL ofthe reaction mixtures were extracted by EtOAc (10 mL). A portion ofEtOAc extract (1 mL) was evaporated, redissolved in acetonitrile (1 mL)and analyzed by reversed phase HPLC (C-18, acetonitrile:water 20:80 to90:10 in 12 min) to determine the area ratio of compound 472 (RT=11.2min) and the product compounds 513i (RT=8.9 min), 513ii (RT=8.9 min) &513iii (RT=9.6 min). A second portion of the EtOAc extract (4 mL) wasevaporated, redissolved in isopropyl alcohol-heptane (1:1, 1 mL) andanalyzed by chiral HPLC (Chiralpak AD, Heptane:Ethanol 85:15, 0.5mL/min) to determine the % ee of compounds 513i (RT=32.2 min) compound513ii (RT=34.8 min) in this system.

TABLE 15 Analysis by Reversed Phase HPLC (Area Time Ratio) Analysis for% ee by HPLC % ee of Microorganism ID Hrs Comp 513i Comp 513ii Comp 472Comp 513i Comp 513ii Comp 513i Streptomyces sp SC1754 24 7% 0% 93% 96.9%3.1% 93.9% 48 12% 0% 88% 96.7% 3.3% 93.3% Streptomyces sp SC3740 24 1%0% 99% 88.0% 12.0% 76.0% 48 2% 0% 98% 85.8% 14.2% 71.7% Nocardia ATCC 245% 0% 95% 93.2% 6.8% 86.3% interforma 21072 48 8% 0% 92% 92.6% 7.4%85.1% Streptomyces ATCC 24 11% 1% 88% 95.7% 4.3% 91.4% antibioticus14890 48 48% 13% 39% 94.1% 5.9% 88.2% Streptomyces ATCC 24 1% 0% 99%82.0% 18.0% 64.1% mediocidicus 13278 48 7% 0% 93% 79.4% 20.6% 58.8%Streptomyces NRRL 24 23% 0% 77% 85.0% 15.0% 70.0% griseus B8090 48 28%0% 72% 85.9% 14.1% 71.8% Amycolatopsis ATCC 24 12% 1% 86% 81.3% 18.7%62.5% orientalis 43490 48 25% 4% 71% 77.4% 22.6% 54.9%

EXAMPLE 514[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(514i) &[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile& (514ii) &(3aα,4β,5α,7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(514iii)

A series of microbial biotransformation reactions were set up togenerate compounds 514i, 514ii & 514iii. The details of the reactionsfor several microorganisms are shown in Table 16 and a general procedureis described below. A 1 mL culture of Streptomyces griseus SC13971 froma frozen vial was used to inoculate 100 mL of medium (0.5% toastednutrisoy, 2% glucose, 0.5% yeast extract, 0.5% K₂HPO₄, 0.5% NaCl,adjusted to pH 7 with 1N HCl (R. V. Smith and J. P. Rosazza, Arch.Biochem. Biophys., 161, 551-558 (1974)) in a 500 mL Erlenmeyer flask andthe flask was incubated at 28° C. at 200 rpm for 3 days. 10 mL of thisculture was used to inoculate 100 mL of medium (as above) in a 500 mLErlenmeyer flask and the flask was incubated at 28° C. at 200 rpm for 1day. For the filamentous fungi Mucor rouxii and Cunninghamellaechinulata, 1 mL of spore suspension, prepared by washing a slant with10 mL water, was used to inoculate 100 mL of medium (as above) in a 500mL Erlenmeyer flask and the flask was incubated at 28° C. at 200 rpm for1 day. Compound 472 (30 mg in 1 mL methanol) was added to each cultureand the incubations were continued for 6 to 10 days. Samples of 10 mL ofthe culture broth in each flask were removed and extracted with ethylacetate (20 mL). Samples of 10 mL of the organic layers were eachindividually evaporated to dryness at 40° C. under a nitrogen stream.The residues were dissolved in 1.2 mL isopropanol and analyzed byreversed phase HPLC (YMC Pak ODS 150×6 mm, 3μ C-18, acetonitrile: water20:80 to 90:10 in 12 min, 1 mL/min, 40° C.) to determine theconcentration of compound 472 (RT=11.2 min) and product compounds 514i(RT=8.9 min), 514ii (RT=8.9 min) & 514iii (RT=9.6 min). The same sampleswere analyzed by chiral HPLC (Chiralpak AD, heptane:ethanol 85:15, 0.5mL/min) to determine the % ee of compounds 514i (RT=32.2 min) compound514ii (RT=34.8 min) in this system.

TABLE 16 time Comp. 472 Comp. 514i Comp 514i Comp514iii strain SC ATCCdays mg/ml mg/ml ee % mg/ml 1. Mucor rouxii 13920 24905 3 0.30 0.01100.00 0.000 6 0.27 0.01 100.00 0.000 2. Streptomyces griseus 1397113273 3 0.29 0.01 100.00 0.000 6 0.30 0.01 100.00 0.000 3.Cunninghamella echinulata 16027 9244 3 0.34 0.02 100.00 0.002 6 0.060.02 100.00 0.001 10 0.16 0.02 100.00 0.001

EXAMPLE 515[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(515)

Microbial transformation of compound 472 to compound 515 was conductedon a 3 L scale in a 5 L fermentor, using Cunninghamella echinulata SC16027 (ATCC 9244) and a medium consisting of the following: 0.5% toastednutrisoy, 2% glucose, 0.5% yeast extract, 0.5% K₂HPO₄, 0.5% NaCl,adjusted to pH 7 with 1N HCl (R. V. Smith and J. P. Rosazza, Arch.Biochem. Biophys., 161, 551-558 (1974)). The fermentor was batched with0.05% SAG antifoam before sterilization. Spore inoculum was prepared bywashing the spores from a 10 day slant culture of Cunninghamellaechinulata SC 16027 (ATCC 9244) with 0.9% saline/0.1% Tween 80. Theinoculum stage was prepared by adding 1 mL of spore inoculum into 100 mLmedium in a 500 mL flask, then the cultures were grown at 28° C. at 200rpm for 1 day. 10% inoculum from the flask was blended in a sterileWaring blender and used to inoculate the sterile fermentor, containing 3L of sterile media. The fermentor was run at 28° C. at 600 rpm and 1 vvmaeration. A sterile solution of three antibiotics was added to thefermentor after inoculation; 12 mg of tetracycline chloride, 12 mg ofkanamycin sulfate, and 60 mg of cephalexin hydrate in 10 mL of deionizedwater. After 22 hours of growth in the fermentor, a sterile substratesolution was added containing 0.75 g of compound 472 dissolved in 30 mLof methanol, this step was repeated two hours later for a total of 0.5g/L of compound 472 in the bioconversion. The fermentation conditionswere maintained at 28° C. at 600 rpm and 1 vvm aeration. pH 6.5 wasmaintained by the automatic addition of 10% H₂SO₄ or 10% NaOH.Periodically, 10 mL aseptic samples were taken and extracted with two 10mL portions of ethyl acetate. The ethyl acetate layer was isolated,dried under a nitrogen stream at 40° C., and the residue was dissolvedin 2.0 mL of isopropyl alcohol. The samples were analyzed by reversephase HPLC (method below) to determine the ratio of compound 472 and theproduct compound 515. In addition, each sample was analyzed by chiralHPLC (method below) in order to determine the % ee of compound 515.During the bioconversion process, a sterile solution of 30% cerelose and1.5% yeast extract was fed into the reaction at ˜5 mL/hour. After 114 hfrom the time of substrate addition, reverse phase HPLC analysisindicated the production of a 78% yield of compound 515. Chiral HPLCanalysis measured the % e.e. of compound 515 at 94.9%. The above processwas repeated in another 3 L bioconversion, and the reaction wasconducted at 28° C. at 600 rpm, 1 vvm aeration, with 0.5 g/L of compound472 input. After 44 h, this reaction gave a 80% yield of compound 515with 95% e.e. The broth was flittered through a pad of HyFlo™ to providea clarified fermentation broth. The broth was flittered through a pad ofHyFlo™ to provide a clarified fermentation broth. Compound 515 wascompletely adsorbed onto 55 g of XAD-16 and extracted back into a 1:1mixture of EtOAc and acetone (3×100 mL) or methyl-tert-butyl ether(3×100 mL). The solvent was removed in vacuo and the resulting residuewas purified by silica pad (5 g), eluting with EtOAc. The desiredfractions were collected and treated with activated carbon (0.5 g) todeclorize the solution and the solvent was removed in vacuo to yield1.27 g of compound 515. Re-crystallization of this material fromEtOAc/heptane (10 mL/20 mL) resulted 950 mg of crystalline compound 515having 97% purity by reverse phase HPLC and 95% ee by chiral HPLC.Reverse Phase HPLC: YMC Pak ODS-A C18 column, 4.6×50 mm, eluting with agradient of: 0 min 20% acetonitrile/80% 0.1% TFA in water, 12 min 90%acetonitrile/10% 0.1% TFA in water, 12.01-15 min 20% acetonitrile/80%0.1% TFA in water, monitoring at 250 nm, 40° C., 5 μL injection volume).Compound 515: RT=8.86 min. Chiral HPLC: CHIRALPAK OD 25×0.46 cm column;isocratic elution with 15% ethanol/85% heptane at 0.5 mL/min, 18° C.,monitoring at 220 nm, injection volume: 20 μL. Compound 515: RT=36.5min.

In an alternate recovery process, the fermentation broth (1 L) from theabove biohydroxylation reaction was filtered and the cake of cells waswashed with 100 mL of water. Clear broth was extracted with ethylacetate (2×600 mL) and the cake of cells was extracted with 400 mL ofethyl acetate. The combined ethyl acetate layers were concentrated andthe resulting residue was dissolved in 5 mL of 1:1 heptane/ethyl acetateand loaded on to silica gel pad pad (70 g in 250 mL fritted glassfilter). The silica gel pad was eluted with a gradient of 80 to 90%EtOAc/heptane. Fractions were collected and the fractions containingcompound 515 were pooled. The solvent was removed in vacuo and resultingproduct was crystallized from EtOAc/heptane to give a 90% yield ofcompound 515 with 98% purity by reverse phase HPLC and 95% ee by chiralHPLC. Reverse Phase HPLC: YMC Pak ODS-A C18 column, 4.6×50 mm, elutingwith a gradient of: 0 min 20% acetonitrile/80% 0.1% TFA in water, 12 min90% acetonitrile/10% 0.1% TFA in water, 12.01-15 min 20%acetonitrile/80% 0.1% TFA in water, monitoring at 250 nm, 40° C., 5 μLinjection volume). Compound 472: RT=11.12 min. Compound 515: RT=8.86min. Chiral HPLC: CHIRALPAK OD 25×0.46 cm column; isocratic elution with15% ethanol/85% heptane at 0.5 mL/min, 18° C., monitoring at 220 nm,injection volume: 20 μL. Compound 472: RT=27.4 min. Compound 515:RT=36.5 min. Compound (514iii) RT=39.1 min.

EXAMPLE 5164-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(516B)

The following Example demonstrates preparation of an intermediate usefulfor preparing compounds of the formula I of the present invention.

A. 3-(4-Cyano-3-trifluoromethylphenylcarbamoyl)acrylic acid (516A)

5-amino-2-cyanobenzotrifluoride (210.6 mmoles; 40.00 g) and butylacetate (80 mL) were added to a 250 mL round bottom flask, followed bythe addition of maleic anhydride (231.9 mmoles, 23.20 g). The resultingsuspension was heated to 60° C. for 3.5 h. The reaction mixture wascooled to 25° C. and then heptane (160 mL) was added dropwise over aperiod of 25 minutes. The resulting suspension was filtered and washedwith a mixture of 4:1, hepatane:butyl acetate (30 mL) and heptane (45mL). The cake was dried in vacuo to give 60 g (95% yield) of compound516A.

B.4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(516B)

Compound 516A (17.42 mmoles, 5.000 g) was added to the reaction flaskfollowed by the addition of zinc bromide (17.58 mmoles, 3.960 g) andthen toluene (50.00 mL, 43.25 g) was added to the mixture. The resultingsuspension was stirred for 20 min. Hexamethyldisilazane (26.35 mmoles,5.560 mL, 4.253 g) was added to this suspension which was then heated to60° C. for 4.5 h. The reaction mixture was diluted with EtOAc (25 mL)and then poured into a 1N HCl solution (30 mL) at 25° C. The organicphase was collected and the aqueous phase was extracted with EtOAc (15mL). The organic phase was isolated, combined with the earlier organicphase and washed consecutively with saturated NaHCO₃ (15 mL), a mixtureof 1:1 water:brine solution (15 mL) and brine (15 mL). The resultingsolution was dried over MgSO₄, filtered and concentrated in vacuo to a50 mL suspension. Heptane (125 mL) was added dropwise to this suspensionwith agitation. The resulting thicker suspension was filtered and washedwith a mixture of 2:1 heptane:toluene (15 mL) and then heptane (15 mL)to give 4 g (85% yield) of compound 516B. HPLC: 100% at 2.11 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm).

EXAMPLES 517 TO 746

Additional compounds of the present invention were prepared byprocedures analogous to those described above. The compounds of Examples517 to 746 have the structures shown in the following Table 17.

Table 17 also provides the compound name, retention time/molecular mass,and the procedure employed for preparation of these compounds. Thechromatography techniques used to determine the compound retention timesof Table 17 are as follows: LC and LCMS were described in Examples 439to 454 (Table 9). The molecular mass of the compounds listed in Table17, where provided, was determined by MS (ES) by the formula m/z.

Retention Ex. Time Min./ Pro. of No. Compound Structure Compound NameMolecular Mass Ex. 517

[3aR-(3aα,4β,7β,7aα)]-4-[4-Ethyloctahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.84LC[M + H]⁺ =391.16 245 & 461 518

[3aS-(3aα,4β,7β,7aα)]-4-[4-Ethyloctahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.84LC[M + H]⁺ =391.16 245 & 461 519

[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(6-Chloro-2-methyl-4-pyrimidinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.04LC[M + H]⁺ =519.0 243 & 244 520

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(6-Chloro-2-methyl-4-pyrimidinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.04LC[M + H]⁺ =519.0 243 & 244 521

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2Hisoindol-2-yl]-1-naphthalenecarbonitrile3.90LC[M + H]⁺ =502.28 245 & 461 522

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]-4-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.37LC[M + H]⁺ =518.28 435, 499 &500 523

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.90LC[M + H]⁺ =502.27 245 & 461 524

[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]-4-ethyloctahydro-5-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.40LC[M + H]⁺ =518.27 435, 499 &500 525

(3aα,4β,7β,7aα)-5-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.32LC[M + H]⁺ =489.26 467 526

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(2-methyl-5-benzothiazolyl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.36LC[M + H]⁺ =540.0 243 & 244 527

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.35LC[M +OAc]⁻ =644.8 243 & 244 528

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(3,4-Dihydro-2,2-dimethyl-4-oxo-2H-1-benzopyran-7-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.37LC[M +OAc]⁻ =391.16 243 & 244 529

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[[5-methyl-2-(2-pyridinyl)-4-thiazolyl]oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.47LC[M + H]⁺ =566.9 243 & 244 530

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[2-(Diethylamino)-6-methyl-4-pyrimidinyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.47LC[M + H]⁺ =556.1 243 & 244 531

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-(2-quinoxalinyloxy)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.39LC[M + H]⁺ =520.6 243 & 244 532

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(2-oxo-1,3-benzoxathiol-5-yl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.35LC[M +OAc]⁻ =600.8 243 & 244 533

(3aα,4β,7β,7aα)-4-[4-[2-[(2,3-Dihydro-2-oxo-5-benzofuranyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.28LC[M +OAc]⁻ =566.6 223 & 250 534

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-8-quinolinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.18LC[M + H]⁺ =553.6 243 & 244 535

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-(5-phenyl-1H-tetrazol-1-yl)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.32LC[M + H]⁺ =521.5 243 & 244 536

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(1H-1,2,3-Benzotriazol-1-yl)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.15LC[M + H]⁺ =493.8 243 & 244 537

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-[2-(1H-indol-4-yloxy)ethyl]-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.05LC[M]⁺ =507.6 243 & 244 538

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(7-Chloro-4-quinazolinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.33LC[M + H]⁺ =555.2 243 & 244 539

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.48LC[M + H]⁺ =552.2 243 & 244 540

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.08LC[M + H]⁺ =524.2 243 & 244 541

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(6-Chloro-9H-purin-9-yl)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.70LC[M + H]⁺ =529.0 243 & 244 542

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-3-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.17LC[M + H]⁺ =504.1 243 & 244 543

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[3-(2-oxo-1-pyrrolidinyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.10LC[M + H]⁺ =552.3 243 & 244 544

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[2-(Dimethylamino)-5,6-dimethyl-4-pyrimidinyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.40LC[M + H]⁺ =542.3 243 & 244 545

(3aα,4β,7β,7aα)-7-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile3.52LC[M + H]⁺ =495.6 424A,204,482F &482G 546

(1aα,2β,2aα,5aα,6β,6aα)-4-[Octahydro-2-(2-hydroxyethyl)-6-methyl-3,5-dioxo-2,6-epoxy-4H-oxireno[f]isoindol-4-yl]-1-naphthalenecarbonitrile2.36LC[M + H]⁺ =391.31 460 & 228 547

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-(3-oxoisoxazolo[5,4-b]pyridin-2(3H)-yl)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.92LC[M +OAc]⁻ =568.6 243 & 244 548

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.18LC[M +OAc]⁻ =596.7 243 & 244 549

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[6-oxo-4-(trifluoromethyl)-1(6H)-pyrimidinyl]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.94LC[M +OAc]⁻ =596.5 243 & 244 550

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[3-Chloro-2-oxo-5-(trifluoromethyl)-1(2H)-pyridinyl]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.39LC[M +OAc]⁻ =629.3 243 & 244 551

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.76LC[M +OAc]⁻ =629.6 243 & 244 552

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(2,3-Dihydro-2,2-dimethyl-3-oxo-7-benzofuranyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.26LC[M +OAc]⁻ =611.5 243 & 244 553

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(2-methyl-1H-indol-4-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.16LC[M + H]⁺ =522.5 243 & 244 554

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-[2-(1H-indol-5-yloxy)ethyl]-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.03LC[M + H]⁺ =506.3 243 & 244 555

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-1,2-dihydro-2-oxo-3-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.85LC[M + H]⁺ =520.5 243 & 244 556

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(5-Chloro-2H-1,2,3-benzotriazol-2-yl)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.53LC[M +OAc]⁻ =586.3 243 & 244 557

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-(5-methyl-2H-1,2,3-benzotriazol-2-yl)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.35LC[M + H]⁺ =508.5 243 & 244 558

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(6-Chloro-1H-1,2,3-benzotriazol-1-yl)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.32LC[M + H]⁺ =528.3 243 & 244 559

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-(6-methyl-1H-1,2,3-benzotriazol-1-yl)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.97LC[M + H]⁺ =508.4 243 & 244 560

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(3,5-Dichloro-2-oxo-1(2H)-pyridinyl)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.22LC[M + H]⁺ =538.3 243 & 244 561

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(6-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.30LC[M + H]⁺ =504.3 243 & 244 562

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(3,5-Dichloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.67LC[M + H]⁺ =596.3 243 & 244 563

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(1,3-Dihydro-3-oxo-2H-indazol-2-yl)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.82LC[M + H]⁺ =509.1 243 & 244 564

[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-7-[2-(1H-indazol-3-yloxy)ethyl]-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.19LC[M + H]⁺ =509.2 243 & 244 565

[3aR-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-[(5-chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.21LC[M + H]⁺ =526.2 481 566

[3aR-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-(5-chloro-3-oxo-1,2-benzisoxazol-2(3H)-yl)ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.81LC[M + H]⁺ =526.2 481 567

[3aR-(3aα,4β,5β,7β,7aα)]-7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-2-(6-benzothiazolyl)hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.80LC[M + H]⁺ =495.2 481 568

[3aS-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-[(5-chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.21LC[M + H]⁺ =526.1 481 569

[3aS-(3aα,4β,5β,7β,7aα)]-2-(6-Benzothiazolyl)-7-[2-(5-chloro-3-oxo-1,2-benzisoxazol-2(3H)-yl)ethyl]hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.84LC[M + H]⁺ =391.16 481 570

[3aS-(3aα,4β,5β,7β,7aα)]-7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-2-(6-benzothiazolyl)hexahydro-5-hydroxy-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.82LC[M + H]⁺ =495.2 481 571

(3aα,4β,5β,7β,7aα)-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.64 & 3.76atropisomersLCMS[M + H]⁺ =518.19 491 572

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.50LC[M + H]⁺ =518.28 491 573

[3aR-(3aα,4β,7β,7aα)]-4-[4-Ethyloctahydro-7-[2-(3-methoxyphenoxy)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile7.49 & 7.75atropisomersLCHRMS[M +CH₃—CO₂]⁻ =555.2144 245C,461 & 462 574

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(3,5-Dimethylphenoxy)ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile8.10 & 8.31atropisomersHRMS[M + CH₃CO₂]⁻ =553.2363 245C,461 & 462 575

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[(2,3-Dihydro-1H-inden-5-yl)oxy]ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile8.17 & 8.37atropisomersHRMS[M + CH₃CO₂]⁻ =565.2326 245C,461 & 462 576

[3aR-(3aα,4β,7β,7aα)]-5-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.45LC[M + H]⁺ =489.0 467 & 487 577

[3aS-(3aα,4β,7β,7aα)]-5-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.45LC[M + H]⁺ =488.99 467 & 487 578

[3aR-(3aα,4β,7β,7aα)]-5-[Octahydro-4-methyl-1,3-dioxo-7-[2-[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.25LC[M + H]⁺ =524.0 467 & 487 579

[3aS-(3aα,4β,7β,7aα)]-5-[Octahydro-4-methyl-1,3-dioxo-7-[2-[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.45LC[M + H]⁺ =523.98 467 & 487 580

[3aR-(3aα,4β,7β,7aα)]-5-[4-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.66LC[M + H]⁺ =529.16 467 & 487 581

[3aS-(3aα,4β,7β,7aα)]-5-[4-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.66LC[M + H]⁺ =529.16 467 & 487 582

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[[2-(Diethylamino)-6-methyl-4-pyrimidinyl]oxy]ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile5.85 & 6.06atropisomersLC[M + H]⁺ =554.26 245C,461 & 462 583

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyano-3-fluorophenoxy)ethyl]-7-ethyloctahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile7.23 & 7.50atropisomersHRMS[M − H]⁻ =508.1682 245C,461 & 462 584

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]-5-ethoxyoctahydro-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.60LC[M + H]⁺ =532.23 223,495 & 496 585

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-4-methyl-1,3-dioxo-5-(2-propenyloxy)-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.68LC[M + H]⁺ =544.23 491 586

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-4-methyl-1,3-dioxo-5-(phenylmethoxy)-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.63LC[M + H]⁺ =594.26 491 587

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-[[6-(methoxymethyl)-2-(2-propynylthio)-4-pyrimidinyl]oxy]ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.02LC[M + H]⁺ =567.31 491 588

[3aR-(3aα,4β,7β,7aα)]-5-[Octahydro-4-methyl-7-[2-(5-methyl-2H-1,2,3-benzotriazol-2-yl)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.37LC[M + H]⁺ =493.24 467 & 487 589

[3aS-(3aα,4β,7β,7aα)]-5-[Octahydro-4-methyl-7-[2-(5-methyl-2H-1,2,3-benzotriazol-2-yl)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.37LC[M + H]⁺ =493.24 467 & 487 590

[3aR-(3aα,4β,7β,7aα)]-5-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.14LC[M + H]⁺ =479.22 467 & 487 591

[3aS-(3aα,4β,7β,7aα)]-5-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.14LC[M + H]⁺ =479.22 467 & 487 592

[3aR-(3aα,4β,5β,7β,7aα)]-7-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile3.38LC[M + H]⁺ =5552.12 482 593

[3aS-(3aα,4β,5β,7β,7aα)]-7-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile3.39LC[M + H]⁺ =552.10 482 594

[3aR-(3aα,4β,5β,7β,7aα)]-7-[7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile3.00LC[M + H]⁺ =521.15 482 595

[3aS-(3aα,4β,5β,7β,7aα)]-7-[7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile2.99LC[M + H]⁺ =521.14 482 596

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyano-3-fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.76LCMS[M + H]⁺ =496.2 496 597

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-(3-methylphenoxy)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.79LCMS[M + H]⁺ =467.2 496 598

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.01LCMS[M + H]⁺ =471.2 496 599

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.98LCMS[M + H]⁺ =471.2 496 600

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.88LCMS[M + H]⁺ =478.2 496 601

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(2-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.42LCMS[M + H]⁺ =478.2 496 602

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(2-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.83LCMS[M + H]⁺ =483.2 496 603

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(3-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.14LCMS[M + H]⁺ =483.2 496 604

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Chlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.09LCMS[M + H]⁺ =487.2 496 605

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Acetylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.20LCMS[M + H]⁺ =495.2 496 606

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[3-(Dimethylamino)phenoxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.94LCMS[M + H]⁺ =496.2 496 607

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(5-isoquinolinyloxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.89LCMS[M + H]⁺ =504.2 496 608

N-[3-[2-[3aR-(3aα,4β,7β,7aα)]-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]phenylacetamide1.97LCMS[M + H]⁺ =510.6 496 609

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-[4-(1H-imidazol-1-yl)phenoxy]ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.81LCMS[M + H]⁺ =519.6 496 610

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[2-(4-morpholinyl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.16LCMS[M + H]⁺ =538.2 496 611

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(3-phenoxyphenoxy)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.89LCMS[M + H]⁺ =545.2 496 612

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(2-pyridinylthio)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.91LCMS[M + H]⁺ =469.6 496 613

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[(3,5-Dichlorophenyl)thio]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.53LCMS[M + H]⁺ =537.1 496 614

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[[7-(trifluoromethyl)-4-quinolinyl]thio]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.49LCMS[M + H]⁺ =588.2 496 615

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[(6-methyl-2-pyridinyl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.79LCMS[M + H]⁺ =467.5 496 616

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.98LCMS[M + H]⁺ =478.2 496 617

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(3,5-Dimethylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-napthalenecarbonitrile1.80LCMS[M + H]⁺ =481.2 496 618

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(2,6-Dimethylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.88LCMS[M + H]⁺ =481.2 496 619

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(4-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.50LCMS[M + H]⁺ =483.2 496 620

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[(2,3-Dihydro-1H-inden-5-yl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.14LCMS[M + H]⁺ =493.3 496 621

3-[2-[[3aR-(3aα,4β,7β,7aα)]-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]benzoicacid,methyl ester 3.99LCMS[M + H]⁺ =511.2 496 622

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Formyl-2-methoxyphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.01LCMS[M + H]⁺ =511.2 496 623

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-[4-(3-hydroxypropyl)phenoxy]ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.93LCMS[M + H]⁺ =511.3 496 624

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(2,3-Dichlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.79LCMS[M + H]⁺ =521.1 496 625

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(1,1-Dioxido-2H-naphtho[1,8-cd]isothiazol-2-yl)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.69LCMS[M + H]⁺ =564.2 496 626

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[(4-Fluorophenyl)thio]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.03LCMS[M + H]⁺ =487.2 496 627

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-[(3-methoxyphenyl)thio]ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.02LCMS[M + H]⁺ =499.2 496 628

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-[(4-methoxyphenyl)thio]ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile1.99LCMS[M + H]⁺ =499.2 496 629

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(3-hydroxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.27LCMS[M + H]⁺ =469.2 496 630

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-[(4-Cyanophenyl)amino]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.56LCMS[M + H]⁺ =477.2 496 631

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3,5-Dimethylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.10LCMS[M + H]⁺ =481.2 496 632

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(3-hydroxy-5-methylphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.56LCMS[M + H]⁺ =483.2 496 633

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Chlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.03LCMS[M + H]⁺ =487.1 496 634

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(2,3-Dihydro-1H-inden-5-yl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.15LCMS[M + H]⁺ =493.2 496 635

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Acetylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.65LCMS[M + H]⁺ =495.2 496 636

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(5-isoquinolinyloxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.67LCMS[M + H]⁺ =504.2 496 637

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(2,3-Dihydro-3-oxo-6-benzofuranyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.90LCMS[M + H]⁺ =509.2 496 638

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(2,3-Dichlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.80LCMS[M + H]⁺ =521.1 496 639

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(3-phenoxyphenoxy)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.54LCMS[M + H]⁺ =545.2 496 640

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(4-pyrimidinyloxy)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.13LCMS[M + H]⁺ =455.2 496 641

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3,4-Dimethylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.19LCMS[M + H]⁺ =481.2 496 642

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(2,3-Dimethylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.80LCMS[M + H]⁺ =481.2 496 643

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-[(4-methoxy-2-pyridinyl)oxy]ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.72LCMS[M + H]⁺ =484.2 496 644

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(2-Chlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.63LCMS[M + H]⁺ =487.1 496 645

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Chlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.07LCMS[M + H]⁺ =487.1 496 646

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(5-Chloro-2-oxo-1(2H)-pyridinyl)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.13LCMS[M + H]⁺ =488.1 496 647

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(2,1,3-Benzoxadiazol-5-yloxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.15LCMS[M + H]⁺ =495.2 496 648

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(7-quinolinyloxy)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.93LCMS[M + H]⁺ =504.2 496 649

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(6-quinolinyloxy)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 4.01LCMS[M + H]⁺ =504.2 496 650

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(2-oxo-1(2H)-quinoxalinyl)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.33LCMS[M + H]⁺ =505.2 496 651

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(4-quinazolinyloxy)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.39LCMS[M + H]⁺ =505.2 496 652

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[4-methyl-2-(1-methylethyl)-6-oxo-1(6H)-pyrimidinyl]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.72LCMS[M + H]⁺ =511.3 496 653

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[(1-phenyl-1H-pyrazol-3-yl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.48LCMS[M + H]⁺ =519.2 496 654

[3a-(3aα,4β,7β,7aα)]-4-[4-[2-(2,4-Dichlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.85LCMS[M + H]⁺ =521.1 496 655

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3,4-Dichlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.86LCMS[M + H]⁺ =521.1 496 656

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3,5-Dichlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.47LCMS[M + H]⁺ =521.1 496 657

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(2,5-Dichlorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.33LCMS[M + H]⁺ =521.1 496 658

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.87LCMS[M + H]⁺ =525.2 496 659

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[[2-(Dimethylamino)-5,6-dimethyl-4-pyrimidinyl]oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 2.71LCMS[M + H]⁺ =526.2 496 660

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[4-(methylsulfonyl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.91LCMS[M + H]⁺ =531.2 496 661

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[3-(4-morpholinyl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.78LCMS[M + H]⁺ =538.2 496 662

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-[4-(methoxymethyl)-6-oxo-2-(2-propynylthio)-1(6H)-pyrimidinyl]ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 4.18LCMS[M + H]⁺ =569.2 496 663

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(3-oxo-1,2-benzisoxazol-2(3H)-yl)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.18LCMS[M + H]⁺ =494.2 496 664

[3aS-(3aα,4β,7β,7aα)]-4-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]-1,2-benzenedicarbonitrile4.30LCMS[M + H]⁺ =503.1 496 665

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyano-3,5-dimethylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.13LCMS[M + H]⁺ =506.2 496 666

[3aS-(3aα,4β,7β,7aα)]-5-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]-1H-indole-3-acetonitrile,trifluoroacetate(1:1) 3.36LCMS[M + H]⁺ =531.2 496 667

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[3-(1-piperazinyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.81LCMS[M + H]⁺ =537.2 496 668

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyano-3-fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.89LCMS[M + H]⁺ =496.2 496 669

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[3-(Dimethylamino)phenoxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.37LCMS[M + H]⁺ =496.2 496 670

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[(5-methyl-1H-1,2,4-triazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.26LCMS[M + H]⁺ =458.2 496 671

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(6-Amino-4-pyrimidinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 2.97LCMS[M + H]⁺ =470.2 496 672

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 3.45LCMS[M + H]⁺ =509.2 496 673

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(4,5-Dichloro-3-pyridazinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.79LCMS[M + H]⁺ =523.1 496 674

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-naphthalenecarbonitrile3.86LCMS[M + H]⁺ =488.4 496 675

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.78LCMS[M + H]⁺ =494.41 496 676

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(2-quinoxalinyloxy)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-napthalenecarbonitrile3.83LCMS[M + H]⁺ =505.43 496 677

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[[6-methyl-2-(1-methylethyl)-4-pyrimidinyl]oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.52LCMS[M + H]⁺ =511.49 496 678

[3aS-(3aα,4β,7β,7aα)]-5-[4-[2-(1,3-Benzodioxol-5-yloxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile 3.327LC[M +H]⁺ =498.24 467 & 487 679

[3aR-(3aα,4β,7β,7aα)]-4-[Octahydro-1,3-dioxo-4-(2-phenoxyethyl)-7-propyl-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile7.77 & 8.01atropisomersLC[M + H]⁺ =481.4 501 680

[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cyanophenoxy)ethyl]octahydro-1,3-dioxo-7-propyl-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile7.42 & 7.68atropisomersLC[M + H]⁺ =506.38 501 681

[3(3aα,4β,7β,7aα)]-4-[4-Butyl-7-[2-(4-cyanophenoxy)ethyl]octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile7.69 & 7.92atropisomersLC[M + H]⁺ =520.38 502 682

[3aR-(3aα,4β,7β,7aα)]-4-[4-Butyloctahydro-1,3-dioxo-7-(2-phenoxyethyl)-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile8.02 & 8.23atropisomersLC[M + H]⁺ =495.33 502 683

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]-4-ethyloctahydro-5-methoxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 7.31 & 7.55atropisomersLC[M + H]⁺ =532.3 504 684

[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]-4-ethyloctahydro-5-methoxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 7.31 & 7.55atropisomersLC[M + H]⁺ =532.3 504 685

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(4-Cyanophenoxy)ethyl]-4-ethyloctahydro-5-methoxy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile6.84 & 7.10atropisomersLC[M + H]⁺ =522.33 504 686

[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-methoxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.37 & 3.52atropisomersLC[M + H]⁺ =518.16 491 687

[3aS-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-methoxy-7-(2-methoxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.57 & 2.75atropisomersLC[M + H]⁺ =421.18 491 688

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(3-hydroxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.38LCMS[M + H]⁺ =469.38 496 689

[3aS-(3aα,4β,5β,7β,7aα)]-5-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.833LC[M + H]⁺ =540.17 485, 486,487 & 488 690

[3aS-(3aα,4β,5β,7β,7aα)]-5-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[6-oxo-4-(trifluoromethyl)-1(6H)-pyrimidinyl]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.59LC[M + H]⁺ =540.16 485, 486,487 & 488 691

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-1,3-dioxo-7-propyl-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile7.91 & 8.15atropisomersLC[M + H]⁺ =516.25 501 692

[3aS-(3aα,4β,7β,7aα)]-4-[4-Butyl-7-[2-[(5-chloro-2-pyridinyl)oxy]ethyl]octahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile8.18 & 8.39atropisomersLC[M + H]⁺ =530.28 502 693

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(3-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.97LCMS[M + H]⁺ =483.1 496 694

N-[3-[2-[3aS-(3aα,4β,7β,7aα)]-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]phenylacetamide3.42LCMS[M + H]⁺ =510.1 496 695

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[3-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.83LCMS[M + H]⁺ =521.1 496 696

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.86LCMS[M + H]⁺ =521.2 496 697

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[[2-(Diethylamino)-6-methyl-4-pyrimidinyl]oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.63LCMS[M + H]⁺ =540.2 496 698

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(5-Chloro-2-benzothiazolyl)thio]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.15LCMS[M]⁺ =560.0 496 699

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(6-Ethoxy-2-benzothiazolyl)thio]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.15LCMS[M + H]⁺ =570.1 496 700

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(2,4-Dimethylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.71LCMS[M + H]⁺ =481.2 496 701

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(2,5-Dimethylphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.79LCMS[M + H]⁺ =481.2 496 702

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-(2-naphthalenyloxy)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.66LCMS[M + H]⁺ =503.2 496 703

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-2-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.72LCMS[M + H]⁺ =507.2 496 704

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(6-Chloro-3-oxo-1,2-benzisoxazol-2(3H)-yl)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.71LCMS[M + H]⁺ =528.1 496 705

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-([1,1′-Biphenyl]-3-yloxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.03LCMS[M + H]⁺ =529.2 496 706

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(2-Dibenzofuranyloxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.51LCMS[M + H]⁺ =543.2 496 707

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-(4-phenoxyphenoxy)ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.73LCMS[M + H]⁺ =545.2 496 708

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[[2-(Dimethylamino)-6-(trifluoromethyl)-4-pyrimidinyl]oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 4.15LCMS[M + H]⁺ =566.2 496 709

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-(3-methylphenoxy)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.17LCMS[M + H]⁺ =466.5 496 710

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-(6-methyl-2-oxo-1(2H)-pyridinyl)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.41LCMS[M + H]⁺ =468.2 496 711

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.10LCMS[M + H]⁺ =471.2 496 712

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Fluorophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.56LCMS[M + H]⁺ =471.2 496 713

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Cyanophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.28LCMS[M + H]⁺ =478.2 496 714

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(4-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.58LCMS[M + H]⁺ =483.2 496 715

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(1H-indol-5-yloxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.40LCMS[M + H]⁺ =492.2 496 716

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(2,3-Dihydro-1-oxo-1H-inden-5-yl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.20LCMS[M + H]⁺ =507.2 496 717

[3aS-(3aα,4β,7β,7aα)]-4-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]benzeneacetamide3.26LCMS[M + H]⁺ =510.2 496 718

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(2-Amino-8-quinolinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 2.77LCMS[M + H]⁺ =519.2 496 719

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-5-oxo-2-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.88LCMS[M + H]⁺ =521.2 496 720

[3aS-(3aα,4β,7β,7aα)]-1-Acetyl-3-[2-[2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]-1H-indole4.03LCMS[M + H]⁺ =534.2 496 721

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[[5-methyl-2-(4-pyridinyl)-4-thiazolyl]oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile,trifluoroacetate(1:1) 4.02LCMS[M + H]⁺ =551.2 496 722

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(2,6-Dimethyl-4-pyrimidinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.74LCMS[M + H]⁺ =483.2 496 723

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(2-Amino-6-methyl-4-pyrimidinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.71LCMS[M + H]⁺ =484.2 496 724

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(1H-indol-7-yloxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.23LCMS[M + H]⁺ =492.2 496 725

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-(7-methyl-3-oxo-1,2-benzisoxazol-2(3H)-yl)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.02LCMS[M + H]⁺ =508.2 496 726

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-[5-hydroxy-3-(2-hydroxyethyl)-1H-indol-1-yl]ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile2.94LCMS[M + H]⁺ =536.2 496 727

N-[3-[2-[[3aS-(3aα,4β,7β,7aα)]-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]phenyl]urea4.26LCMS[M + H]⁺ =511.2 496 728

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[[2-Amino-6-(methoxymethyl)-4-pyrimidinyl]oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.18LCMS[M + H]⁺ =514.2 496 729

N-[3-[2-[[3aS-(3aα,4β,7β,7aα)]-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]phenyl]-N′-(1,1-dimethylethyl)urea3.13LCMS[M + H]⁺ =567.2 496 730

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-(3-hydroxy-5-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.22LCMS[M + H]⁺ =499.2 496 731

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(6-Amino-2-methyl-4-pyrimidinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.19LCMS[M + H]⁺ =484.2 496 732

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3,5-Dihydroxyphenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.73LCMS[M + H]⁺ =485.1 496 733

[3aS-(3aα,4β,7β,7aα)]-4-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol-4-yl]ethoxy]benzamide4.11LCMS[M + H]⁺ =496.2 496 734

[3aR-(3aα,4β,5β,7β,7aα)]-5-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.847LC[M + H]⁺ =540.14 485, 486,487 & 488 735

[3aR-(3aα,4β,5β,7β,7aα)]-5-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[6-oxo-4-(trifluoromethyl)-1(6H)-pyrimidinyl]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.577LCMS[M + H]⁺ =540.14 485, 486,487 & 488 736

[3aR-(3aα,4β,5β,7β,7aα)]-5-[7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.867LCMS[M + H]⁺ =514.16 485, 486,487 & 488 737

[3aS-(3aα,4β,5β,7β,7aα)]-5-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.24LCMS[M + H]⁺ =545.12 485, 486,487 & 488 738

[3aR-(3aα,4β,5β,7β,7aα)]-5-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.25LCMS[M + H]⁺ =545.12 485, 486,487 & 488 739

[3aS-(3aα,4β,5β,7β,7aα)]-5-[7-[2-(5-Chloro-3-oxo-1,2-benzisoxazol-2(3H)-yl)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.863LCMS[M + H]⁺ =545.12 485, 486,487 & 488 740

[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-[(6-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile4.04LCMS[M + H]⁺ =528.1 496 741

[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-methyl-7-[2-[(7-methyl-1,2-benzisoxazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile3.94LCMS[M + H]⁺ =508.1 496 742

(αS)-6-Methoxy-α-methyl-2-naphthaleneaceticacid,[3aR-(3aα,4β,5β,7β,7aα)]-2-[4-cyano-3-(trifluoromethyl)phenyl]octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindol-5-ylester [M − H]⁻ = 591.3 483 743

[3aS-(3aα,4β,5β,7β,7aα)]-5-[Octahydro-5-hydroxy-4-methyl-7-[2-[(4-methyl-2-oxo-2H-1-benzopyran-7-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.89LCMS[M + H]⁺ =552.19 486, 486,487 & 488 744

[3aS-(3aα,4β,5β,7β,7aα)]-5-[7-[2-[[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.46LCMS[M + H]⁺ =573.12 485, 486,487 & 488 745

[3aS-(3aα,4β,5β,7β,7aα)]-5-[7-[2-(3-Fluorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.05LCMS[M + H]⁺ =488.03 485, 486,487 & 488 746

[3aS-(3aα,4β,5β,7β,7aα)]-5-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.98LCMS[M + H]⁺ =538.23 485, 486,487 & 488

EXAMPLE 747[3aR-(3aα,4β,7β,7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-4-methyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl]-1-naphthalenecarbonitrile(747)

Dess-Martin periodinane (122 mg, 0.29 mmol, prepared as described inIshiharaa, J., T. Fukuzakia, et al. Tetrahedron Letters 40(10),1907-1910 (1999)) was added to a solution of the compound 490A (120 mg,0.24 mmol) in dichloromethane (2.5 mL) under nitrogen and the mixturewas stirred for 4 h. The reaction was half concentrated under a streamof nitrogen and was applied on a flash cartridge (Jones 2 g) with celiteon top and was eluted with chloroform:heptane (9:1) tochloroform:acetone (4:1) to give 148 mg of a still impure white solid.The solid was disolved in dichloromethane (5 mL) and heptane (3 mL) andthe precipitate was filtered over 1 g silica and was eluted withdichloromethane to chloroform:acetone (4:1). Fractions 3-9 (58.8 mgwhite solid) was almost pure and fractions 10-13 (68 mg white foam) werestill impure. Fractions 3-9 were purified over silica (1 g) usingheptane to heptane:ethyl acetate (1:1) as eluant to give 35.8 mg (30%yield) compound 747 as a white solid. Fractions 10-13 were purified byadding ˜400 mg of silica to an excess solution of crude compound 747 inethyl acetate and heptane and concentrating it. The silica was then puton top of a preconditioned (heptane) silica column (1 g) and was elutedwith a gradient from heptane to heptane ethyl acetate (1:1) to give anadditional 36.7 mg (31% yield) of compound 747 as a white solid. HPLC:94% at 3.46 & 3.59 min (atropisomers, retention time) (YMC S5 ODS 4.6×50mm, 4 mL min, 4 min gradient 100% A to 100% B (A: 10% methanol, 89.1%water, 0.1% TFA; B: 10% water, 89.1% methanol, 0.1% TFA, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 502.11 [M+H]⁺.

EXAMPLE 748(3aα,5β,7β,7aα)-4-[Octahydro-5-hydroxy-4,7-dimethy-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-isoquinolinecarbonitrile(748D)

A. 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-isoquinoline-1-carbonitrile(748A)

A mixture of compound 470D (200 mg, 1.18 mmol) and maleic anhydride (470mg, 4.7 mmol) in glacial acetic acid (5 μL) was heated to reflux for 4hours. After removing the volatiles in vacuo, the residue waspartitioned between ethyl acetate (50 mL) and water (50 mL). The organiclayer was washed with saturated sodium bicarbonate solution (2×50 mL)and brine (50 mL). After drying over magnesium sulfate, the organiclayer was filtered through a 1×5 cm plug of silica gel. The filtrate wasconcentrated to afford 263 mg (90%) of 748a as an off-white solid. HPLC:99% at 1.12 min (Phenomenex 5 micron ODS 4.6×30 mm, 10%-90% aqueousmethanol over 2 minute gradient with 0.1% TFA, detecting at 254 nm). MS(ES): m/z 250.2 [M+H]⁺.

B.(3aα,4β,7β,7aα)-4-(1,3,3a,4,7,7a-Hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-1-isoquinolinecarbonitrile(748B)

A mixture of compound 748A (250 mg, 1 mmol) and 2,5-dimethylfuran (4 mL)was heated to 60° C. for 2 h. At 15 min, the reaction mixture becamehomogeneous. A precipitate formed at 45 minutes. After cooling to 25°C., the reaction mixture was diluted with hexane and the filter cake waswashed with ethyl ether:hexane, 1:1. Drying under high vacuum afforded270 mg (78%) of compound 748B as a light yellow solid. ¹HNMR-400 MHz(CDCl₃): δ 8.55 (s, 1H), 8.54 (m, 1H), 7.86 (m, 3H), 6.45 (s, 2H), 3.18(s, 2H), 1.81 (s, 6H).

C.(1aα,2β,2aα,5aα,6β,6aα)-4-[Octahydro-2,6-dimethyl-3,5-dioxo-2,6-epoxy-4H-oxireno[f]isoindol-4-yl]-1-isoquinolinecarbonitrile(748C)

m-CPBA, (70%, 110 mg, 0.45 mmol) was added to a solution of compound748B (100 mg, 0.29 mmol) in 3 mL of dichloromethane at 25° C. After 1 h,additional m-CPBA, (70%, 110 mg, 0.45 mmol) was added and the reactionmixture was stirred an additional 18 h. After partitioning the reactionmixture between ethyl acetate (30 mL) and water (30 mL), the organiclayer was washed with saturated sodium bisulfite solution (30 mL),saturated sodium bicarbonate solution (2×30 mL) and brine (30 mL). Thesample was dried over magnesium sulfate and concentration to yield 103mg (98%) of compound 748C as an off-white solid. HPLC: 99% at 1.09 &1.22 min (atropisomers, retention time) (Phenomenex 5 micron ODS 4.6×30mm, 10%-90% aqueous methanol over a 2 min gradient with 0.1% TFA,detecting at 254 nm). MS (ES): m/z 362.07 [M+H]⁺.

D.(3aα,4β,5β,7β,7aα)-4-[Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-isoquinolinecarbonitrile(748D)

A 0.5 M solution of bis(cyclopentadienyl)titanium chloride in THF (1.2mL, 0.6 mmol) was added dropwise over 20 min to a well stirredsuspension of compound 748C (103 mg, 0.29 mmol) in THF (2.5 mL) and1,4-cyclohexadiene (1.2 mL) at 60° C. After stirring 1 h at 60° C., thereaction mixture was partitioned between 1N HCl (40 mL) and ethylacetate (50 mL). The pH of the aqueous layer was adjusted to 7 withsolid sodium bicarbonate. After extracting the aqueous with ethylacetate, the combined organic layers were dried over sodium sulfate.Decolorizing carbon (˜1 g) was added and the mixture was allowed tostand for 18 h. Filtration and concentration of the filtrate in vacuoafforded a yellow oil that was chromatographed on a 2.5×15 cm silica gelcolumn, using dichloro-methane:acetone, 6:4 as the mobile phase.Concentration of the product containing fractions in vacuo gave apartially purified residue that was subjected to preparative thin layersilica gel chromatography, using dichloromethane:acetone, 6:4 as themobile phase. Extraction of the desired band with CH₂Cl₂, filtration andconcentration of the filtrate in vacuo yielded 3 mg (31%) of compound748D as an off-white solid. HPLC conditions: 95% at 1.46 min (Phenomenex5 micron ODS 4.6×30 mm, 10%-90% aqueous methanol over 2 minute gradientwith 0.1% TFA, detecting at 254 nm). MS (ES): m/z 364.19 [M+H]⁺.

EXAMPLE 749(3aα,4β,7β,7aα)-4-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-thiophenecarbonitrile(749C)

A. 2-Cyano-4-nitrothiophene (749Ai) & 2-Cyano-5-nitrothiophene (749Aii)

Fuming nitric acid (21 mL) was slowly added to glacial acetic acid (105mL) and the mixture was then cooled in an ice-bath. 2-Cyanothiophene(7.98 g, 73.1 mmol) was dissolved in 20 mL of acetic anhydride and addeddropwise to the above acid mixture such that the temperature did notexceed 25° C. Upon completion of the addition, the reaction mixture waswarmed to 22° C. and stirred for 48 h. The reaction was poured over 400mL of ice and extracted with 200 mL of diethylether. The ether layer wasisolated, washed with water, followed by brine and dried over MgSO₄.Filtration and concentration in vacuo gave a sticky, orange residuewhich was purified by column chromatography using 1:1 hexanes/methylenechloride as the eluent to give 1.69 g (15%) of compound 749Ai as a whitesolid and 1.71 g (15%) of compound 749Aii as a yellow crystallinesubstance. Compound 749Ai: HPLC: 0.73 minutes (retention time)(Phenomenex column 30×4.6 mm eluting with 10-90% aqueous methanol over 2minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm). Compound749Aii: HPLC: 99% at 0.89 minutes (retention time) (Phenomenex column30×4.6 mm eluting with 10-90% aqueous methanol over 2 minutes containing0.1% TFA, 5 mL/min, monitoring at 220 nm).

B. 4-Amino-2-cyanothiophene (749B)

To a 100 mL 3-necked flask was added compound 749Ai (1.42 g, 9.21 mmol)dissolved in ethyl acetate (20 mL) followed by a 10% acetic acidsolution (20 mL). The biphasic mixture was heated to 65° C. and theniron powder (2.95 g, 52.9 mmol) was added portion-wise over 5 minutes.After stirring for 1.5 h at 65° C., the reaction was filtered through abed of Celite and the pad was washed with ethyl acetate. The organiclayer was separated, washed with water (3×20 mL), brine and dried overMgSO₄. Filtration and concentration in vacuo gave a dark amber residuewhich was purified by column chromatography using 30% diethylether/methylene chloride as the eluent to give 84 mg (73%) of compound749B as a brown solid. HPLC: 93.4% at 0.26 minutes (retention time) (YMCS5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm).

C.(3aα,4β,7β,7aα)-4-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-thiophenecarbonitrile(749C)

To a Pyrex tube was added compound 749B (0.06 g, 0.5 mmol), toluene (1mL), triethylamine (0.25 g, 0.35 mL, 2.5 mmol), MgSO₄ (0.15 g, 1.3mmol), and compound 20A. The tube was sealed with a teflon cap andheated overnight at 145° C. The reaction was cooled, diluted withmethylene chloride and filtered through Celite. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography using 10% ether/methylene chloride as the eluent to give14 mg (95%) of compound 749C as a light yellow crystalline solid. HPLC:94.6% at 2.6 minutes (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm. MS (ES): m/z 303.05[M+H]⁺.

EXAMPLE 750(3aα,4β,7β,7aα)-5-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-thiophenecarbonitrile(750B)

A. 5-Amino-2-cyanothiophene (750A)

To a 100 mL 3-necked flask was added compound 749Aii (1.63 g, 10.1 mmol)dissolved in ethyl acetate (20 mL) followed by a 10% solution of aceticacid (20 mL). The biphasic mixture was heated to 65° C. and then ironpowder (2.95 g, 52.9 mmol) was added portion-wise over 5 minutes. Afterstirring for 1.5 h at 65° C., the reaction was filtered through a bed ofCelite and the pad was washed with ethyl acetate. The organic layer wasseparated, washed with water (3×20 mL), brine and dried over MgSO₄.Filtration and concentration in vacuo gave a dark amber residue whichwas purified by column chromatography using 10% diethyl ether/methylenechloride as the eluent to give 87 mg (66%) of compound 750A as a brownsolid. HPLC: 94.2% at 1.05 minutes (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

B.(3aα,4β,7β,7aα)-5-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-thiophenecarbonitrile(750B)

To a Pyrex tube was added compound 750A (0.06 g, 0.5 mmol), toluene (1mL), triethylamine (0.25 g, 0.35 mL, 2.5 mmol), MgSO₄ (0.15 g, 1.3mmol), and compound 20B. The tube was sealed with a teflon cap andheated overnight at 145° C. The reaction was cooled, diluted withmethylene chloride and filtered through Celite. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography using 10% ether/methylene chloride as the eluent to yield143 mg (96%) of compound 750B as a light yellow crystalline solid. HPLC:92.7% at 2.93 minutes (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm. MS (ES): m/z 303.21[M+H]⁺.

EXAMPLE 751[3aS-(3aα,4β,7β,7aα)]-Hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxyisobenzofuran-1,3-dione(751)

To a solution of compound 471Dii (2.36 g, 6.21 mmol) in tetrahydrofuran(THF, 20 mL) cooled in an ice-bath (˜5° C.) was added, in one portion,aq 1M NaOH solution (10 mL, 10 mmol). The resulting light yellowreaction mixture was stirred for 30 min then acidified by addition of aq1M HCl solution (12 mL, 12 mmol) and partitioned between water (100 mL)and EtOAc (40 mL). The aqueous layer was separated and extracted withEtOAc (25 mL). The organic phases were combined, dried rapidly oversodium sulfate and filtered, rinsing with hot THF to dissolve someprecipitated solid product. The filtrate was concentrated in vacuo togive the crude ring opened amido-acid intermediate as a white solid. Aslurry of the crude material suspended in 60 mL of dry THF and 25 mL ofglacial HOAc and was heated with stirring to 60° C. during which timethe mixture became homogeneous. After 9 h, the reaction mixture wascooled and concentrated in vacuo to give a pale yellow solid. The solidwas triturated with 30 mL of toluene, warmed (˜50° C.), then allowed tocool to rt. The insoluble product was collected on a Buchner funnel,washed with toluene and dried under vacuum to afford compound 751 (75%)as a white solid. 400 MHz ¹H NMR (DMSO-d₆) δ 1.34 (s, 3H), 1.34 (m, 1H),1.45 (s, 3H), 2.32 (dd, J=7.3, 13.1, 1H), 3.20 (d, J=7.3, 1H), 3.28 (d,J=7.2, 1H), 3.79 (m, 1H), 5.11 (d, J=6.1, 1H); 100 MHz ¹³C NMR (DMSO-d₆)δ 169.6, 86.7, 82.3, 72.8, 52.9, 50.3, 46.5, 16.0, 11.2. The absolutestereochemistry of compound 751 is established by the knownstereochemistry of the intermediate compound 471Dii and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE.

EXAMPLE 752[3aR-(3aα,4β,7β,7aα)]-Hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxyisobenzofuran-1,3-dione(752)

Compound 752 was synthesized as described in example 751 with theexception that the starting compound 471Di was utilized as the startingmaterial rather than compound 471Dii. 400 MHz ¹H NMR (DMSO-d₆) δ 1.34(s, 3H), 1.34 (m, 1H), 1.45 (s, 3H), 2.32 (dd, J=7.3, 13.1, 1H), 3.20(d, J=7.3, 1H), 3.28 (d, J=7.2, 1H), 3.79 (m, 1H), 5.11 (d, J=6.1, 1H);100 MHz ¹³C NMR (DMSO-d₆) δ 169.6, 86.7, 82.3, 72.8, 52.9, 50.3, 46.5,16.0, 11.2. The absolute stereochemistry of compound 752 is establishedby the known stereochemistry of the intermediate compound 471Di and theretention of configuration therein. The absolute stereochemistry is asdrawn in the above FIGURE.

EXAMPLE 753[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile(753G)

A. 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(453A)

A mixture of 3-trifluoromethyl-4-cyano-aniline (24.0 g, 129 mmol) andmaleic anhydride (14.0 g, 143 mmol) in 50 mL of acetic acid was heatedat 115° C. overnight. A precipitate was obtained during the heatingperiod. The reaction was allowed to stand at rt for an additionalovernight period. The solid was removed by filtration, the filter cakewas washed with diethyl ether and dried to give 21 g (79 mmol, 61%) ofcompound 753A as an off white solid. HPLC: 100% at 2.11 min (retentiontime) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoringat 220 nm).

B.(3aα,4β,7β,7aα)-4-(1,3,3a,4,7,7a-Hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(753B)

A slurry of4-(2,5-dihydro-2,5-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(15.0 g, 56.35 mmol) and 2,5-dimethylfuran (32.5 g, 338 mmol) wasstirred at 60° C. for 3 h, followed by continued stirring for another 14h at 23° C. The mixture was diluted with cold (˜5° C.) toluene (15 mL)and the resulting off white solid was collected by filtration whilecold. The filter cake was washed with cold toluene (20 mL) and dried at23° C. in vacuum oven for 24 h to provide compound 753B (18:6 g, 91%yield) with a purity of 98.7% as judged by HPLC.

C.[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(753C)

A slurry of compound 753B (5.0 g, 13.81 mmol), allylpalladium chloridedimer (10 mg, 0.027 mmol) and(R)-2-methoxy-2′-diphenylphosphino-1,1′-binaphthyl (R-MOP, 26 mg, 0.055mmol) in THF (14 mL) was purged with nitrogen and cooled to 10° C. Tothe above mixture, was added trichlorosilane (3.7 g, 27.62 mmol) slowlyover a period of 10 min and the resulting heterogeneous mixture wasstirred for 24 h at 10° C. The mixture was diluted with THF (85 mL) andfurther cooled to −20° C. To the above mixture, a solution oftriethylamine (9.76 g, 96.67 mmol) in ethanol (6.35 g, 138.1 mmol) wasadded slowly keeping the temperature <25° C. and stirred for another 2 hat rt. The white solid was filtered and the filter cake was washed withTHF (50 mL) and the filtrate was evaporated under the reduced pressure.The oily residue was dissolved in ethyl acetate (100 mL) and stirred at23° C. in the presence of trithiocyanuric acid (TMT, 500 mg) andcharcoal (500 mg) for 5 h. The slurry was filtered through a pad ofcelite and silica gel and the filtrate was evaporated under the reducedpressure. The residue was dissolved in a mixture of THF (175 mL) andmethanol (125 mL), and to this mixture was added anhydrous potassiumfluoride (2.0 g, 34.5 mmol), potassium hydrogencarbonate (6.9 g, 69mmol), followed by ureahydrogen peroxide adduct (6.5 g, 69 mmol). Thissuspension was stirred at rt for 14 h and an additional amount ofpotassium fluoride (800 mg, 13.81 mmol), potassium hydrogencarbonate(1.38 g, 13.81 mmol) and urea-hydrogen peroxide adduct (2.59 g, 27.62mmol) was added. Stirring continued for another 12 h and the slurry wasfiltered and the filter cake was washed with ethyl acetate (100 mL). Thefiltrate was washed consecutively with 10% aqueous sodiumhydrogensulfite (50 mL×2), water (50 mL) and brine (50 mL). The solventwas evaporated under the reduced pressure to provide a light brown foam.Column chromatography of this foam using silica gel and EtOAc-heptane(2:3) afforded compound 753C (4.72 g, 90%, >99% pure by HPLC) as an offwhite solid. This material has an enantiomeric purity of >96% ee bychiral HPLC and LC-MS: m/z 379 (M+H-). The absolute stereochemistry ofcompound 753C was established by comparison to existing material ofknown stereochemistry as described in Example 483.

D.[1S-(1β,2α,3α,4β,6β)]-3-[[(4-Cyano-3-(trifluoromethyl)phenyl)amino]carbonyl]-6-hydroxy-1,4-dimethyl-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid &[1R-(1β,2α,3α,4β,5β)]-3-[[(4-Cyano-3-(trifluoromethyl)phenyl)amino]carbonyl]-5-hydroxy-1,4-dimethyl-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid (753Di &753Dii)

Compound 753C (25.0 g, 65.7 mmol) was dissolved in THF (100 mL) at 22°C. and 1 N NaOH (100 mL) was added. After 1 h, THF (100 mL), 1 N HCl(110 mL) and brine (100 mL) were added. The mixture was then extractedonce with EtOAc (200 mL) and twice with 1:1 THF/EtOAc (200 mL). Thecombined organics were dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give compounds 753Di and 753Dii (1:1 by HPLC)as a white solid. No purification was necessary. HPLC: 100% at 2.217 and2.413 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

E.[3aR-(3aα,4β,7β,7aα)]-Hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxyisobenzofuran-1,3-dione(753E)

Compounds 753Di and 753Dii were suspended in a mixture of THF (500 mL)and AcOH (200 mL) and heated to 60° C. for 16 h. The reaction becamehomogenous after 4 h. The reaction was cooled to 22° C. and concentratedin vacuo. Toluene (200 mL) was then added and the mixture was heated to90° C. for 4 h until all product was dissolved. The mixture was thencooled to 22° C. and left standing for 20 h. Compound 753E precipitatesfrom solution over the 20 h period. The resulting solid was filtered andrinsed with toluene followed by drying in vacuo. A yield of 11.93 g ofcrude compound 753E was obtained as an off-white solid. Crude compound753E (10 g) was dissolved in 350 ml of warm EtOAc (the solution wasturbid), and then 5 g of decolorizing carbon was added and the mixturewas stirred at rt for 40 mins. After filtering through celite, thefilter cake was washed with hot EtOAc (2×50 ml). Concentration of thefiltrate afforded an off-white solid that was dissolved in 40 ml of hotacetonitrile. After carefully adding 200 ml of ethyl ether, 300 ml ofhexane was added and the flask was allowed to stand 18 hrs at rt.Filtration and drying afforded 8.32 g of compound 753E as a colorlesscrystalline solid. ¹H NMR (DMSO-d⁶): δ=5.11 (d, 1H, J=6.0 Hz), 3.78 (dd,1H, J=7.2, 30.6 Hz), 3.27 (d, 1H, J=7.2 Hz), 3.20 (d, 1H, J=7.3 Hz),2.27 (dd, 1H, J=7.3, 13.1 Hz), 1.44 (s, 3H), 1.33 (s, 3H) and 1.32 ppm(m, 1H).

F. 4-Amino-2-iodo-benzonitrile (753F)

2-Iodo-4-nitro-benzonitrile (1.00 g, 3.65 mmol, was prepared by themethod given in J. Med. Chem. 2000, 43, 3344-47) was dissolved in THF(20 mL) at 60° C. with mechanical stirring. EtOH (25 mL) was then addedfollowed by aq NH₄Cl (0.293 g, 5.48 mmol in 20 mL H₂O). Iron powder (325mesh, 0.815 g, 14.6 mmol) was then added with vigorous stirring. After 2h, reaction was complete. Cooled to 22° C. and filtered through celiterinsing with EtOAc. The mixture was then concentrated to ˜20 mL and thendiluted with EtOAc (200 mL) and washed once with 1 N NaOH (50 mL), oncewith brine (50 mL) and dried over anhydrous MgSO₄, to give, compound753F (0.710 g) as a light yellow solid. No additional purification wasneeded. HPLC: 99% at 2.147 min (retention time) (YMC S5 ODS column,4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

G.[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile(753G)

A mixture of compound 753E (1.60 g, 7.57 mmol), compound 753F (1.32 g,5.41 mmol), 4 Å molecular sieves (2.0 g) in dimethylacetamide (8 mL) wasstirred in a 175° C. oil bath for 4 h. The resulting dark mixture wascooled, diluted with EtOAc (50 mL) then filtered to remove sieves andrinsed with EtOAc. The filtrate was partitioned between EtOAc (50 mL)and water (75 mL). The organic phase was separated, washed with water(2×75 mL), brine (50 mL), then diluted with tetrahydrofuran (20 mL),dried over sodium sulfate and concentrated in vacuo to give a solidfoam. The crude material was triturated with diethyl ether (100 mL) thenstirred for 1.5 h. The solid precipitate was collected on a Buchnerfunnel then suspended in diethyl ether (50 mL) and stirred for 16 h. Theresulting solid was collected on a Buchner funnel, rinsed with diethylether and dried under vacuum (90° C.) to afford compound 753G (67%) asan off-white solid. HPLC: 96% at 3.00 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 438.90 [M+H]⁺. The absolute stereochemistry of compound 753Gis established by the known stereochemistry of the intermediate compound753C and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 754[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile(754)

A mixture of compound 751 (850 mg, 4.01 mmol), 4-cyano-3-iodo-aniline(975 mg, 4.01 mmol), 4 Å molecular sieves (1.2 g) in dimethylacetamide(4.5 mL) was stirred in a 175° C. oil bath for 4 h. The resulting darkmixture was cooled, filtered to remove sieves and rinsed with EtOAc. Thefiltrate was partitioned between EtOAc (50 mL) and water (50 mL). Theorganic phase was separated, washed with water (2×50 mL), brine (25 mL),dried over sodium sulfate and concentrated in vacuo. The crude materialwas dissolved in tetrahydrofuran and purified by silica gel flashchromatography, eluting with 1:4 acetone/methylene chloride to give animpure white solid. The impure material was suspended in diethyl ether(75 mL), stirred for 18 h then collected on a Buchner funnel to afford650 mg (37%) of compound 754 as a white solid. HPLC: 100% at 2.90 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 438.95 [M+H]⁺. The absolutestereochemistry of compound 754 is established by the knownstereochemistry of the intermediate compound 751 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 755

A solution of compound 471Di (80 mg, 0.21 mmol), ethyl isocyanate (30mg, 0.43 mmol) and 4-dimethyaminopyridine (5 mg, 0.04 mmol) in drytetrahydrofuran (1 mL) was heated to 55° C. for 2 h, then additionalethyl isocyanate (30 mg) was added and heated for another 2 h. A finalportion of EIC (30 mg) was added, then after 16 h the reaction mixturewas cooled, concentrated in vacuo and purified by silica gel flashchromatography on SiO₂ eluting with 2:1 EtOAc/heptane to give 80 mg(86%) of compound 755 as a white solid. HPLC: 94% at 3.51 min (retentiontime) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 min containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 452.29 [M+H]⁺. The absolutestereochemistry of compound 755 is established by the knownstereochemistry of the intermediate compound 471Di and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 756

A solution of compound 471Dii (80 mg, 0.21 mmol), ethyl isocyanate (100mg, 1.4 mmol) and 4-dimethyaminopyridine (8 mg, 0.07 mmol) in drytetrahydrofuran (2 mL) was heated to 60° C. for 16 h, then cooled, MeOHwas added and the solution was concentrated in vacuo. The reactionmixture was purified by silica gel flash chromatography, eluting with2:1 EtOAc/heptane to give 84 mg (90%) of compound 756 as a white solidfoam. HPLC: 94% at 3.54 min (retention time) (YMC S5 ODS column, 4.6×50mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 452.34[M+H]⁺. The absolute stereochemistry of compound 756 is established bythe known stereochemistry of the intermediate compound 471Dii and theretention of configuration therein. The absolute stereochemistry is asdrawn in the above FIGURE and rendered by the nomenclature.

EXAMPLE 757

A. (757A)

A mixture of compound 471Di (620 mg, 1.63 mmol), silver(I) oxide (3.78g, 16.3 mmol), allyl iodide (2.74 g, 16.3 mmol) and dry MeCN (15 mL) wasstirred rapidly at 75-80° C. for 7.5 h. The resulting mixture was cooledand filtered though a pad of Celite rinsing with EtOAc. The filtrate wasconcentrated in vacuo and the crude material purified by silica gelflash chromatography on SiO₂ eluting with 1:1 EtOAc/heptane to give 570mg (83%) of compound 757A as a glass. HPLC: 96% at 3.72 min (retentiontime) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoringat 220 nm). MS (ES): m/z 421.27 [M+H]⁺.

B. (757B)

To a mixture of compound 757A (85 mg, 0.20 mmol),4-methylmorpholine-N-oxide (26 mg, 0.22 mmol) and acetone (1.6 mL) at rtwas added water (0.4 mL) and then 2.5% osmium tetroxide solution int-butanol (17 mg, 0.002 mmol). The reaction mixture was stirred for 5 h,then filtered through a pad of Florosil. The filtrate was concentratedin vacuo and the residue partitioned between EtOAc and 1M aq HClsolution. The organic phase was separated, dried over sodium sulfate,concentrated in vacuo and the crude material purified by silica gelflash chromatography on SiO₂ eluting with 2:1 acetone/heptane to givecompound 757B (52 mg, 55%) as a white solid. HPLC: 100% at 3.11 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 455 [M+H]⁺. The absolutestereochemistry of compound 757B is established by the knownstereochemistry of the intermediate compound 471Di and the retention ofconfiguration there in. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 758

To a solution of compound 757A (45 mg, 0.11 mmol), carbon tetrachloride(0.50 mL), acetonitrile (0.5 mL) and water (0.75 mL) at rt was addedsodium periodate (94 mg, 0.44 mmol) then after several minutes,ruthenium(III) chloride hydrate (50 mg, 0.24 mmol). After 30 min thedark mixture was partitioned between methylene chloride (20 mL) andwater (20 mL). The mixture was filtered to remove solids, then theorganic phase was separated, dried over sodium sulfate and concentratedin vacuo. The crude material purified by silica gel flash chromatographyon SiO₂ eluting with 1:20 MeOH/EtOAc then 1:5:100 HOAc/MeOH/EtOAc togive compound 758 (19 mg, 36%) as a white solid foam. HPLC: 99% at 3.31min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 rm). MS (ES): m/z 437.23 [M−H]⁻. The absolutestereochemistry of compound 758 is established by the knownstereochemistry of the intermediate compound 471Di and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 759

To a solution of compound 471Di (100 mg, 0.26 mmol) and triethylamine(50 mg, 0.50 mmol) in dry methylene chloride (3 mL) cooled in anice-bath was added ethyl chloroformate (40 μL, 0.40 mmol). The reactionwas warmed to rt for 2 h and an additional portion of ethylchloroformate (40 μL), triethylamine (50 mg), 4-dimethylaminopyridine(10 mg, 0.08 mmol) was added. The reaction mixture was stirred for 18 hat rt, then partitioned between 25 mL of EtOAc and 25 mL of 1M aq HClsolution. The organic phase was separated, washed with 1M aq HCl (2×25mL), brine (1×25 mL), dried (sodium sulfate) and concentrated in vacuo.Purification by silica gel flash chromatography eluting with 1:1EtOAc/heptane followed by recrystallization (EtOAc/heptane) afforded 76mg (65%) of compound 759 as a white solid. HPLC: 100% at 3.85 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 453.01 [M+H]⁺. The absolutestereochemistry of compound 759 is established by the knownstereochemistry of the intermediate compound 471Di and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 760[3aS-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-2-methyl-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1.3(2H)-dione(760D)

A. N-(4-Chloro-3-trifluoromethylphenyl)-2,2-dimethylpropionamide (760A)

To a solution of commercially available4-chloro-3-(trifluoromethyl)aniline (15.0 g, 76.7 mmol) in anhydrous THF(200 mL) cooled to 0-5° C. was added triethylamine (11.7 mL, 84.4 mmol)followed by pivaloyl chloride (10.4 mL, 84.4 mmol) over 30 min. The icebath was removed and the mixture stirred at rt for 1 h. The mixture wasdiluted with ether and filtered. The filtrate was washed with water (2×)and brine, dried over MgSO₄, filtered and concentrated. The residue wastriturated with hexanes and the solid was filtered and dried in vacuo toafford compound 760A (20.4 g, 95%); MS (ES): m/z=280 [M+1]⁺.

B.N-(4-Chloro-2-methyl-3-trifluoromethylphenyl)-2,2-dimethylpropionamide(760B)

To a solution ofN-(4-chloro-3-trifluoromethylphenyl)-2,2-dimethylpropionamide (2.29 g,8.19 mmol) in anhydrous THF (25 mL) cooled to 0-5° C. was added asolution of 1.6M n-butyllithium in hexanes (12.3 mL, 19.7 mmol) slowlyso that the reaction temperature was maintained below 5° C. The solutionwas stirred at 0-5° C. for 1.5 h. A solution of iodomethane (0.56 mL,9.01 mmol) in petroleum ether (2 mL) was added over 20 min whilemaintaining the temperature below 5° C. The suspension was stirred at0-5° C. for 1 h and diluted with water and ether. The aqueous layer wasextracted with ether and the combined organic layers washed with brine,dried over MgSO₄, filtered and concentrated. The residue waschromatographed (silica gel) eluting with CH₂Cl₂ to afford compound 760B(1.60 g, 67%). MS (ES): m/z=294 [M+1]⁺.

C. 4-Chloro-2-methyl-3-trifluoromethylaniline (760C)

N-(4-Chloro-2-methyl-3-trifluoromethylphenyl)-2,2-dimethyl-propionamide1.0 g, 3.4 mmol) was added to a 1:1 mixture (15 mL) of concentrated HCland ethanol and heated at reflux for overnight. The reaction was cooledand concentrated in vacuo to give a tan solid which was then partitionedbetween EtOAc and saturated NaHCO₃. The organic layer was separated,washed with water, brine, dried (Na₂SO₄), filtered and concentrated togive compound 760C (0.54 g, 76%) as a brown oily solid.

D.[3aS-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-2-methyl-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(760D)

To a Pyrex sealable tube was added4-chloro-2-methyl-3-trifluoromethylaniline (0.1 g, 0.48 mmol), compound751 (0.15 g, 0.72 mmol), TEA (0.24 g, 0.33 mL, 2.4 mmol), MgSO₄ (0.14 g,1.2 mmol), and toluene (0.5 mL). The reaction was heated in the sealedtube at 150° C. for 18 h. The cooled reaction was diluted with EtOAc,filtered, concentrated and purified by Prep-TLC using CH₂Cl₂ as eluentto give compound 760D (0.078 g, 40%) as an off-white solid. HPLC: 90% at3.26 min(YMC S5 ODS column) eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over a 4 min gradient monitoring at 220nm. MS (ES): m/z 404.01 [M+H]⁺. The absolute stereochemistry of compound760D is established by the known stereochemistry of the intermediatecompound 751 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 761[3aR-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-2-methyl-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(761)

To a Pyrex sealable tube was added compound 760C (0.1 g, 0.48 mmol),compound 752 (0.15 g, 0.72 mmol), TEA (0.24 g, 0.33 mL, 2.4 mmol), MgSO₄(0.14 g, 1.2 mmol), and toluene (0.5 mL). The reaction was heated in thesealed tube at 150° C. for 18 h. The cooled reaction was diluted withEtOAc, filtered, concentrated and purified by SiO₂ Prep-TLC using CH₂Cl₂as eluent to give compound 761 (0.056 g, 29%) as an off-white solid.HPLC: 90% at 3.27 min(YMC S5 ODS column) eluting with 10-90% aqueousmethanol containing 0.2% phosphoric acid over a 4 min gradientmonitoring at 220 nm. MS (ES): m/z 403.91 [M+H]⁺. The absolutestereochemistry of compound 761 is established by the knownstereochemistry of the intermediate compound 752 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 762

A. 3-Methoxypyridine-1-oxide (762A)

3-Methoxypyridine (20.08 g, 209 mmol) was dissolved in 100 mL of aceticacid. 30% H₂O₂ (28.3 mL, 275 mmol) was added and the reaction mixturewas heated at 70° C. for six h. The cooled reaction mixture wasconcentrated and the residue dissolved in CH₂Cl₂ and stirred overnightwith 20 g of solid potassium carbonate. The mixture was filtered andconcentrated to give compound 762A (25.2 g, 100%) as a light yellowsolid which was characterized by ¹H NMR and carried on to the next step.

B. 2-Cyano-3-methoxypyridine (762B)

3-Methoxypyridine-1-oxide (25.2 g, 209 mmol) was dissolved inacetonitrile (260 mL). Trimethylsilycyanide (66.35 g, 669 mmol) andtriethylamine (45.13 g, 446 mmol) were added and the reaction mixtureheated at reflux for overnight. The cooled solution was concentrated invacuo to give a brown solid which was partitioned between CH₂Cl₂ and 3MNa₂CO₃. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography using 1:1 EtOAc/hexanes as eluent. Compound762B was isolated (17.63 g, 63%) as a light yellow solid. HPLC: 96.2% at1.37 min(YMC S5 ODS column) eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over a 4 min gradient monitoring at 220nm. MS (ES): m/z 134.88 [M+H]⁺.

C. 2-Cyano-3-methoxy-5-nitropyridine (762C)

2-Cyano-3-methoxypyridine (17.63 g, 131.4 mmol) was dissolved in CH₂Cl₂(400 mL) and cooled in an ice bath. Tetrabutylammonium nitrate (52.02 g,170.8 mmol) and trifluoroacetic anhydride (35.88 g, 170.8 mmol) weredissolved in 200 mL of CH₂Cl₂ and added in a thin stream via additionfunnel. The mixture was warmed to 23° C. and stirred for 60 h. Thereaction mixture was stirred for one h with saturated sodiumbicarbonate. The organic layer was separated, washed with brine, dried(MgSO₄), filtered, concentrated in vacuo, and purified by silica gelcolumn chromatography using CH₂Cl₂ as eluent to give compound 762C(18.07 g, 79%) as a light yellow crystalline solid. HPLC: 100% at 1.67min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS(ES): m/z 179.93 [M+H]⁺.

D. 5-Amino-2-cyano-3-methoxypyridine (762D)

2-Cyano-3-methoxy-5-nitropyridine (1.0 g, 5.6 mmol) was dissolved in 1:1EtOAc/AcOH (10 mL) and heated to 65° C. Iron powder (1.61 g, 28 mmol,325 mesh) was added and the mixture stirred for two h. The mixture wasfiltered though Celite and the filtrate concentrated in vacuo. Theresidue was partitioned between EtOAc and saturated aqueous sodiumbicarbonate. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and concentrated. The residue was purified by SiO₂Prep-TLC using CH₂Cl₂ as the eluent to give the compound 762D (0.805 g,97%) as an off-white solid. HPLC: 100% at 1.31 min(YMC S5 ODS column)eluting with 10-90% aqueous methanol containing 0.2% phosphoric acidover a 4 min gradient monitoring at 220 nm. MS (ES): m/z 149.90 [M+H]⁺.

E. (762E)

5-Amino-2-cyano-3-methoxypyridine (0.1 g, 0.67 mmol), 4 Å molecularsieves (0.4 g), compound 751 (0.142 g, 0.67 mmol), andN,N-dimethylacetamide (0.67 mL) were combined in a sealable Pyrex tubeand heated at 170° C. for 1 h. The cooled reaction mixture was dilutedwith EtOAc and filtered. The filtrate was washed 3× with 1:1 saturatedNH₄Cl/water and then brine. The filtrate was dried over Na₂SO₄,filtered, concentrated and purified by Prep-TLC using 4:1chloroform/acetone as the eluent to give the compound 762E (0.062 g,27%) as a white solid. HPLC: 94% at 1.85 min(YMC S5 ODS column) elutingwith 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4min gradient monitoring at 220 nm. MS (ES): m/z 344.02 [M+H]⁺. Theabsolute stereochemistry of compound 762E is established by the knownstereochemistry of the intermediate compound 751 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 763[3aR-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile(763F)

A. 3-Bromopyridine-1-oxide (763A)

3-Bromopyridine (11.06 g, 70 mmol), 30% H₂O₂ (14 mL, 140 mmol), andmethyltrioxorhenium (0.035 g, 0.14 mmol) were added to 28 mL of CH₂Cl₂and stirred at rt overnight. A 25 mg portion of manganese dioxide wasadded and the reaction was stirred until the evolution of oxygen wascomplete (˜1 h). The organic layer was separated, washed with brine,dried over MgSO₄, filtered, and concentrated in vacuo to give compound673A (9.84 g (81%) as a yellow oil.

B. 3-Bromo-2-cyanopyridine (763B)

3-Bromopyridine-1-oxide was converted to compound 763B as described inexample 762B. The crude product was purified by silica gelchromatography using CH₂Cl₂ as eluent to give compound 763B (6.64 g,65%) as an off-white solid. The product was characterized by ¹H NMR.

C. 3-Bromo-2-cyano-5-nitropyridine (763C)

3-Bromo-2-cyanopyridine was converted to compound 763C as described inexample 762C. The crude product was purified by silica gelchromatography using 20% hexanes/CH₂Cl₂ as eluent to give compound 763C(1.27 g, 16%) as an off-white solid. The product was characterized by ¹HNMR.

D. 2-Cyano-5-nitro-3-trifluoromethylpyridine (763D)

3-Bromo-2-cyano-5-nitropyridine (0.23 g, 1 mmol) was dissolved in DMF (3mL). copper iodide (0.023 g, 0.12 mmol) and methyl2,2-difluoro-2-(fluorosulfonyl)acetate (0.1 g, 0.5 mmol) were added andthe reaction mixture heated at 80° C. for 7 h. Additional methyl2,2-difluoro-2-(fluorosulfonyl)acetate (0.05 g, 0.25 mmol) was added andheating at 80° C. was continued for an additional 8 h. The cooledreaction mixture was poured into water to give a dark oil. Water wasdecanted and the oil was dissolved in EtOAc and washed with water andbrine. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography using CH₂Cl₂ as eluent to compound 763D (0.065 g, 43%) asa yellow oil. HPLC: 90% at 2.09 min(YMC S5 ODS column) eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 mingradient monitoring at 220 nm.

E. 5-Amino-2-cyano-3-trifluoromethylpyridine (763E)

2-Cyano-5-nitro-3-trifluoromethylpyridine (0.065 g, 0.3 mmol) wasreacted in the same manner as described in example 762D to give thedesired compound 763E (0.046 g, 82%) as a gold colored solid aftertrituration with ether. HPLC: 100% at 2.07 min(YMC S5 ODS column)eluting with 10-90% aqueous methanol containing 0.2% phosphoric acidover a 4 min gradient monitoring at 220 nm. MS (ES): m/z 187.82 [M+H]⁺.

F.[3aR-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile(763F)

5-Amino-2-cyano-3-trifluoromethylpyridine (0.044 g, 0.24 mmol) wasreacted with compound 752 (0.087 g, 0.41 mmol) according to theprocedure described for the synthesis of compound 762. The crude productwas purified by SiO₂ Prep-TLC using 15% acetone/CHCl₃ as eluent to givecompound 763F (0.058 g, 65%) as an off-white solid. HPLC: 92% at 2.58min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS(ES): m/z 382.33 [M+H]⁺. The absolute stereochemistry of compound 763Fis established by the known stereochemistry of the intermediate compound752 and the retention of configuration there in. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 764[3aS-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile(764)

5-Amino-2-cyano-3-trifluoromethylpyridine (0.2 g, 1.07 mmol) was reactedwith compound 751 (0.386 g, 1.82 mmol) according to the proceduredescribed in example 763F. The crude product was purified by SiO₂Prep-TLC using 15% acetone/CHCl₃ as the eluent to give compound 764(0.293 g, 72%) as an off-white solid. HPLC: 92% at 2.58 min(YMC S5 ODScolumn) eluting with 10-90% aqueous methanol containing 0.2% phosphoricacid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 382.23[M+H]⁺. The absolute stereochemistry of compound 764 is established bythe known stereochemistry of the intermediate compound 751 and theretention of configuration therein. The absolute stereochemistry is asdrawn in the above FIGURE and rendered by the nomenclature.

EXAMPLE 765 765D

A. 2-Hydroxy-3-iodo-5-nitropyridine (765A)

2-Hydroxy-5-nitropyridine (7.0 g, 50 mmol) was suspended in 100 mL of20% sulfuric acid and then treated with potassium iodate (4.2 g, 19.6mmol) dissolved in 10 mL of water. The mixture was heated to 100° C. andpotassium iodide (8.0 g, 48.2 mmol) dissolved in 20 mL of water wasadded dropwise over one h. The reaction mixture turns a purplish-red anda precipitate forms. After 0.5 h, the reaction mixture is cooled andfiltered. The solid is stirred for 15 min with 10% sodium meta-bisulfitesolution, filtered, washed with water and dried at 80° C. overnight on avacuum pump to give the desired compound 765A (12.32 g, 92%) as a yellowsolid. The product was characterized by ¹H NMR.

B. 2-Chloro-3-iodo-5-nitropyridine (765B)

2-Hydroxy-3-iodo-5-nitropyridine (2.55 g, 9.5 mmol), phosphorouspentachloride (2.60 g, 12 mmol) and phosphorous oxychloride (2 mL) werecombined in a flask under nitrogen and heated to 140° C. for 45 mins.The cooled reaction mixture was poured over ice to give a solid whichwas partitioned between CH₂Cl₂ and water. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered, and the solventwas removed in vacuo to give compound 765B (2.25 g, 83%) as a yellowsolid. HPLC: 98.5% at 2.75 min(YMC S5 ODS column) eluting with 10-90%aqueous methanol containing 0.2% phosphoric acid over a 4 min gradientmonitoring at 220 nm.

C. 5-Amino-2-chloro-3-iodopyridine (765C)

2-Chloro-3-iodo-5-nitropyridine (0.25 g, 0.88 mmol) was reacted withiron powder (0.25 g, 4.4 mmol) in the manner described in example 762D.Removal of the solvent in vacuo gave compound 765C (0.172 g, 77%). as agolden yellow solid. HPLC: 100% at 2.32 min(YMC S5 ODS column) elutingwith 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4min gradient monitoring at 220 nm. MS (ES): m/z 255.03 [M+H]⁺.

D. (765D)

5-Amino-2-chloro-3-iodopyridine (0.06 g, 0.24 mmol) and compound 752(0.085 g, 0.4 mmol) was reacted as previously described in example 762E.The crude product obtained after workup was purified by SiO₂ Prep-TLCusing 10% acetone/CHCl₃ as eluent to give compound 765D (0.067 g, 62%)as an off-white foam. HPLC: 95% at 2.65 min(YMC S5 ODS column) elutingwith 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4min gradient monitoring at 220 nm. MS (ES): m/z 448.96 [M+H]⁺. Theabsolute stereochemistry of compound 765D is established by the knownstereochemistry of the intermediate compound 752 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 766[3aR-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-3-(trifluoromethyl)pyridinyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(766C)

A. 2-Chloro-5-nitro-3-trifluoromethylpyridine (766A)

2-Chloro-3-iodo-5-nitropyridine (1.0 g, 3.5 mmol), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (0.35 g, 1.82 mmol), and copperiodide (0.083 g, 0.44 mmol) were reacted in DMF (10 mL) according to themethod described in example 763D. The crude product was purified bysilica gel chromatography using 30% CH₂Cl₂/hexane as the eluent to givecompound 766A (0.278 g, 35%) as a colorless oil. The product wascharacterized by ¹H NMR and ¹⁹F NMR.

B. 5-Amino-2-chloro-3-trifluoromethylpyridine (766B)

2-Chloro-5-nitro-3-trifluoromethylpyridine (0.16 g, 0.68 mmol) and ironpowder (0.2 g, 3.42 mmol, 325 Mesh) were reacted as described in example762D. Purification of the crude product by Prep-TLC using 10%ether/CH₂Cl₂ as eluent gave compound 766B (0.098 g, 73%) as a yellowsolid. HPLC: 89% at 2.52 min(YMC S5 ODS column) eluting with 10-90%aqueous methanol containing 0.2% phosphoric acid over a 4 min gradientmonitoring at 220 nm. MS (ES): m/z 197.01 [M+H]⁺.

C.[3aR-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-3-(trifluoromethyl)pyridinyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(766C)

5-Amino-2-chloro-3-trifluoromethylpyridine (0.045 g, 0.23 mmol) andcompound 751 (0.085 g, 0.4 mmol) were reacted as described in example762E. After workup, the crude product was purified by Prep-TLC using 10%acetone/CHCl₃ as the eluent to give compound 766C (0.038 g, 42%) as anoff-white solid. HPLC: 100% at 2.92 min(YMC S5 ODS column) eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 mingradient monitoring at 220 nm. MS (ES): m/z 391.06 [M+H]⁺. The absolutestereochemistry of compound 766C is established by the knownstereochemistry of the intermediate compound 751 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 767

5-Amino-2-chloro-3-iodopyridine (0.06 g, 0.24 mmol) and compound 752(0.085 g, 0.4 mmol) were reacted as described in example 762E. The crudereaction product was purified by Prep-TLC using 20% acetone/CHCl₃ as theeluent to give compound 767 (0.061 g, 58%) as a yellow solid. HPLC: 100%at 2.64 min(YMC S5 ODS column) eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over a 4 min gradient monitoring at 220nm. MS (ES): m/z 449.02 [M+H]⁺. The absolute stereochemistry of compound767 is established by the known stereochemistry of the intermediatecompound 752 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 768[3aS-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-3-(trifluoromethyl)pyridinyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(768)

6-Chloro-5-trifluoromethyl-pyridin-3-ylamine (0.045 g, 0.23 mmol) andcompound 752 (0.085 g, 0.4 mmol) were reacted as described in example762E. The crude product was purified by SiO₂ Prep-TLC using 10%acetone/CHCl₃ as the eluent to give compound 768 (0.048 g, 54%) as awhite solid. HPLC: 100% at 2.91 min(YMC S5 ODS column) eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 mingradient monitoring at 220 nm. MS (ES): m/z 391.21 [M+H]⁺. The absolutestereochemistry of compound 768 is established by the knownstereochemistry of the intermediate compound 752 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 769

A. 5-Amino-3-bromo-2-cyanopyridine (769A)

3-Bromo-2-cyano-5-nitropyridine (0.4 g, 1.75 mmol) and iron powder (0.51g, 8.8 mmol, 325 Mesh) were reacted as described in example 762D. Thecrude solid obtained by trituration with ether was purified by SiO₂Prep-TLC using 4:1 CH₂Cl₂/ether as eluent to give compound 769A (0.16 g,(65%) as an off-white solid. HPLC: 100% at 1.77 min(YMC S5 ODS column)eluting with 10-90% aqueous methanol containing 0.2% phosphoric acidover a 4 min gradient monitoring at 220 nm. MS (ES): m/z 197.93 [M+H]⁺.

B. (769B)

5-Amino-3-bromo-2-cyanopyridine (0.06 g, 0.3 mmol) and compound 752(0.096 g, 0.45 mmol) were reacted as previously in example 762E. Thecrude product was purified by SiO₂ Prep-TLC using 20% acetone/CHCl₃ asthe eluent to give compound 769B (0.036 g, 30%) as an off-white solid.HPLC: 100% at 2.29 min(YMC S5 ODS column) eluting with 10-90% aqueousmethanol containing 0.2% phosphoric acid over a 4 min gradientmonitoring at 220 nm. MS (ES): m/z 393.33 [M+H]⁺. The absolutestereochemistry of compound 769B is established by the knownstereochemistry of the intermediate compound 752 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 770

5-Amino-3-bromo-2-cyanopyridine (0.06 g, 0.3 mmol) and compound 751(0.096 g, 0.45 mmol) were reacted as previously in example 762E. Thecrude product was purified by SiO₂ Prep-TLC using 20% acetone/CHCl₃ togive compound 770 (0.038 g (31%) as an off-white solid. HPLC: 99.2% at2.28 min(YMC S5 ODS column) eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over a 4 min gradient monitoring at 220nm. MS (ES): fn/z 392.27 [M]⁺. The absolute stereochemistry of compound770 is established by the known stereochemistry of the intermediatecompound 751 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 771

A. 3-Fluoropyridine-1-oxide (771A)

3-Fluoropyridine (9.71 g, 100 mmol), 30% H₂O₂ (20 mL, 200 mmol), andmethyltrioxorhenium (0.13 g, 0.5 mmol) were reacted in 40 mL of CH₂Cl₂according to the same procedure described in example 760C. Filtrationand concentration of the solvent in vacuo gave compound 771A (8.79 g,78%) as a yellow solid.

B. 2-Cyano-3-fluoropyridine (771B)

3-Fluoropyridine-1-oxide (10.0 g, 88.4 mmol), trimethylsilylcyanide(26.32 g, 265.3 mmol), and triethylamine (17.89 g, 177 mmol) werereacted in 90 mL of acetonitrile utilizing the procedure described inexample 762B. Purification of the crude by silica gel chromatographyusing CH₂Cl₂ as eluent gives compound 771B (7.5 g, 70%) as a lightyellow solid.

C. 2-Cyano-3-fluoro-5-nitropyridine (771C)

2-Cyano-3-fluoropyridine (6.5 g, 53.2 mmol), tetrabutylammonium nitrate(21.07 g, 69.2 mmol), and trifluoroacetic anhydride (14.53 g, 69.2 mmol)were reacted in 245 mL of CH₂Cl₂ utilizing the procedure described inexample 762C. Purification of the crude by silica gel chromatographyusing 20% hexanes/CH₂Cl₂ gave compound 771C (0.12 g, 1.3%) as a yellowoil.

D. 5-Amino-2-cyano-3-fluoropyridine (771D)

2-Cyano-3-fluoro-5-nitropyridine (0.12 g, 0.72 mmol) and iron powder(0.21 g, 3.6 mmol, 325 Mesh) were reacted in 1:1 EtOAc/AcOH (10 mL)utilizing the procedure described in example 762D. Trituration of thecrude product with ether gave compound 771D (0.093 g, 94%) as a paleyellow solid. HPLC: 99% at 1.27 min(YMC S5 ODS column) eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 mingradient monitoring at 220 nm. MS (ES): m/z 138.02 [M+H]⁺.

E. (771E)

5-Amino-2-cyano-3-fluoropyridine (0.45 g, 0.33 mmol) and compound 752(0.104 g, 0.49 mmol) were reacted in 0.33 mL of dimethylacetamideutilizing the procedure described in example 762E. The crude residue waspurified by Prep-TLC using 20% acetone/CHCl₃ as the eluent, yieldingcompound 771E (0.026 g, 23%) as a pale peach-colored solid. HPLC: 90.2%at 1.97 min(YMC S5 ODS column) eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over a 4 min gradient monitoring at 220nm. MS (ES): m/z 332.2 [M+H]⁺. The absolute stereochemistry of compound771E is established by the known stereochemistry of the intermediatecompound 752 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 772

A. 2-Cyano-3-methyl-5-nitropyridine (772A)

Commercially available 2-cyano-3-methylpyridine (2.36 g, 20 mmol),tetrabutylammonium nitrate (6.7 g, 22 mmol) and trifluoroaceticanhydride (4.20 g, 20 mmol) were reacted in 65 mL of CH₂Cl₂ utilizingthe procedure described in example 762B. Purification of the crude bysilica gel chromatography using 20% hexanes/CH₂Cl₂ as the eluent givescompound 772A (1.05 g (32%) as a light yellow solid.

B. 5-Amino-2-cyano-3-methylpyridine (772B)

2-Cyano-3-methyl-5-nitropyridine (0.2 g, 1.23 mmol) was dissolved in 6mL of 90% ethanol and calcium chloride (0.07 g, 0.64 mmol) was addedfollowed by iron powder (0.62 g, 11.1 mmol, 325 Mesh). The heterogeneousmixture was stirred for one h. The mixture was filtered though Celiteand concentrated to give compound 772B (0.13 g, 81%) as a light-brownsolid.

C. (772C)

5-Amino-2-cyano-3-methylpyridine (0.067 g, 0.5 mmol), compound 20A(0.103 g, 0.53 mmol), MgSO₄ (0.15 g, 1.25 mmol), triethylamine (0.25 g,2.5 mmol) and 1 mL of toluene were combined in a sealed tube and heatedat 145° C. for 16 h. The cooled mixture was diluted with CH₂Cl₂,filtered, and purified by silica gel chromatography using 5%ether/CH₂Cl₂ as the eluent to give compound 772C (0.055 g, 35%) as anoff-white solid. HPLC: 100% at 2.49 min(YMC S5 ODS column) eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 mingradient monitoring at 220 nm. MS (ES): m/z 312.2 [M+H]⁺.

EXAMPLE 773

A. 2-Cyano-3,4-dimethyl-5-nitropyridine (773A)

2-Cyano-3-methyl-5-nitropyridine (0.33 g, 2 mmol) was dissolved in 10 mLof THF and cooled in a dry ice/acetone bath under nitrogen.Methylmagnesium bromide (1.33 mL, 4 mmol) was added via syringe overfive mins. The reaction was stirred for 2 h at −70° C. DDQ (0.068 g, 3mmol) in 7 mL of THF was added and the mixture warmed to 25° C. Thesolvent was removed in vacuo and the residue was purified by silica gelchromatography using CH₂Cl₂ as the eluent to give compound 773A (0.15 g,42%) as a red oil.

B. 5-Amino-2-cyano-3,4-dimethylpyridine (773B)

2-Cyano-3,4-dimethyl-5-nitropyridine (0.15 g, 0.85 mmol), calciumchloride (0.05 g, 0.42 mmol), and iron powder (0.44 g, 7.8 mmol, 325Mesh) were reacted as described in example 772B. Purification of thecrude product by silica gel chromatography using 1:1 ether/CH₂Cl₂ as theeluent gave compound 773B (0.054 g, 50%) as a yellow solid.

C. (773C)

5-Amino-2-cyano-3,4-dimethylpyridine (0.05 g, 0.34 mmol) and compound20A (0.1 g, 0.5 mmol) were reacted as described in example 772C. Thecrude product obtained after filtration though Celite was purified bysilica gel chromatography using 10% ether/CH₂Cl₂ as the eluent to givecompound 773C (0.33 g, 30%). as a yellow solid. HPLC: 90% at 2.58min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS(ES): m/z 326.22 [M+H]⁺.

EXAMPLE 774[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&[3aS(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(774Bi and 774Bii)

A.[3aR-(3aα,4β,5α,7β,7aα)]-4-[5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile&[3aS(3aα,4β,5α,7β,7aα)]-4-[5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(774Ai & 774Aii)

Racemic compound 222C was separated into its enantiomers by normal phasepreparative chiral HPLC (CHIRALPAK AD 5×50 cm column; eluting with 7%EtOH in hexanes (isocratic) at 50 mL/min) to give the faster elutingcompound 774Ai (18 mins) and the slower eluting compound 774Aii.

B.[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&[3aS-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(774Bi & 774Bii)

774Ai and 774Aii (0.12 g, 0.25 mmol) were each dissolved in 2 mL of THFand 2 mL of 10% HCl/MeOH was added and the reactions stirred overnightat rt. Saturated sodium bicarbonate and EtOAc were added and the organiclayer was separated, washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give compound 774Bi (0.084 mg, 88%) andcompound 774Bii (0.076 g, 82%). as white solids. Compound 774Bi: HPLC:100% at 2.89 min(YMC S5 ODS column) eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over a 4 min gradient monitoring at 220nm. MS (ES): m/z 381.19 [M+H]. Compound 774Bii: HPLC: 100% at 2.89min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS(ES): m/z 381.16 [M+H]⁺. The absolute stereochemistry of compounds 774Bi& 774Bii has not been established. Although each compound represents asingle antipode, the nomenclature and structure shown does not reflectthe absolute stereochemistry of the compound.

EXAMPLE 775 775F

A. 3-Chloropyridine-1-oxide (775A)

Commercially available 3-chloropyridine (11.36 g, 100 mmol) wasdissolved in 60 mL of acetic acid and 30% hydrogen peroxide (15 mL) wasadded. The reaction mixture was heated to 70° C. for 16 h. The cooledreaction mixture was diluted with chloroform and stirred with solidpotassium carbonate. The mixture was filtered and solvent removed invacuo to give compound 775A (10.21 g, 79%) as a yellow-green oil.

B. 3-Chloro-2-cyanopyridine (775B)

3-Chloropyridine-1-oxide (2.59 g, 20 mmol), trimethylsilyl cyanide (5.95g, 60 mmol), and triethylamine (4.05 g, 40 mmol) were combined in 40 mLof acetonitrile and reacted as described in example 763A. The solventwas removed in vacuo and the residue partitioned between CH₂Cl₂ and 3Mpotassium carbonate. The organic layer was separated, washed with brine,dried (MgSO₄), and concentrated in vacuo. Purification of the crudeproduct by silica gel chromatography using 5% ether/CH₂Cl₂ as the eluentgave compound 775B (1.84 g, 67%) as a white crystalline solid. HPLC:100% at 1.64 min(YMC S5 ODS column) eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over a 4 min gradient monitoring at 220nm. MS (ES): m/z 139.0 [M+H]⁺.

C. 3-Chloro-2-cyano-5-nitropyridine (775C)

3-Chloro-2-cyanopyridine (1.75 g, 12.7 mmol), tetrabutylammonium nitrate(5.02 g, 16.5 mmol), and trifluoroacetic anhydride (3.15 g, 15 mmol)were combined in 65 mL of CH₂Cl₂ and reacted as described in example762C. The crude product was purified by silica gel chromatography usingCH₂Cl₂ as the eluent to give compound 775C (0.43 g, 16%) as a paleyellow solid.

D. 5-Amino-3-chloro-2-cyanopyridine (775D)

3-Chloro-2-cyano-5-nitropyridine (0.35 g, 1.9 mmol), iron powder (0.56g, 10 mmol, 325 Mesh) and calcium chloride (0.06 g, 0.55 mmol) werecombined in 10 mL of 90% ethanol and as described in example 772B.Purification of the crude product via silica gel chromatography using10% ether/CH₂Cl₂ as the eluent gives compound 775D (0.14 g, 43%) as alight brown solid. HPLC: 95.5% at 1.69 min(YMC S5 ODS column) elutingwith 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4min gradient monitoring at 220 nm. MS (ES): m/z 154.03 [M+H]⁺.

E. (775E)

5-Amino-3-chloro-2-cyanopyridine (0.05 g, 0.33 mmol) and compound 20A(0.07 g, 0.36 mmol) were reacted as described in example 772C. The crudeproduct obtained after workup was purified by silica gel chromatographyusing 5% ether/CH₂Cl₂ to give compound 775E (0.054 g, 50%) as anoff-white solid. HPLC: 97.6% at 2.86 min(YMC S5 ODS column) eluting with10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 mingradient monitoring at 220 nm. MS (ES): m/z 332.16 [M+H]⁺.

EXAMPLE 776

To a clear solution of compound 741Di (190 mg, 0.5 mmol) in anhydrousdioxane (3.5 mL) was added Burgess Reagent (143 mg, 0.6 mmol) at rtunder Argon. After the mixture was stirred at rt for 70 min,bis(cyclopentadienyl) titanium dichloride (137 mg, 0.55 mmol) was added.The mixture was stirred at 100° C. for 1 day, then cooled to rt. H₂O anda saturated aqueous solution of KHSO₄ were added. The mixture wasextracted with EtOAc (3×). The combined extracts were dried over Na₂SO₄and concentrated under reduced pressure. Purification by silica gelflash chromatography eluting with EtOAc/heptane (gradient from 1:4 to1:0 ratio) gave compound 776 (170 mg, 74%) as a yellow glassy solid.HPLC: 99% at 3.27 min (retention time) (YMC S5 ODS-A column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 458[M−H]⁻. The absolute stereochemistry of compound 776 is established bythe known stereochemistry of the intermediate compound 741Di and theretention of configuration therein. The absolute stereochemistry is asdrawn in the above FIGURE and rendered by the nomenclature.

EXAMPLE 777

A. Pyrazolo[1,5-a]pyridine-4-carboxylic acid ethyl ester (777A)

To a clear solution of 2-methyl-nicotinic acid ethyl ester (50.6 g, 306mmol) in anhydrous methylene chloride (200 mL) was addedOmesitylenesulfonylhydroxylamine (73 g, 337 mmol; prepared according toa literature procedure described in Krause; J. G., Synthesis 1972, 140);in portions at 0° C. The solution obtained was stirred at 0° C. for 15min, and then at rt for 1 h. Concentration under reduced pressure gave ayellow solid. After the solid was dissolved in anhydrous DMF (300 mL),N,N-dimethylformamide dimethyl acetal (122 mL, 918 mmol) was added at 0°C. The mixture was stirred at 0° C. for 15 min, and then at 90° C. for 3h. The reaction mixture was concentrated under reduced pressure, mixedwith H₂O (200 mL), and extracted with Et₂O (3×180 mL). The combinedorganic solutions were washed sequentially with brine (50 mL), 1Naqueous HCl (50 mL), and brine (50 mL), and dried over Na₂SO₄.Filtration through a SiO₂ column, which was then eluted with 30% EtOAcin heptane, gave compound 777A (43.3 g, 74%) as a yellow solid. HPLC:80% at 3.20 min (retention time) plus 20% corresponding methyl ester at2.83 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 191 [M+H]⁺.

B. Pyrazolo[1,5-a]pyridine-4-carboxylic acid (777B)

To a stirred mixture of pyrazolo[1,5-a]pyridine-4-carboxylic acid ester(35.1 g, 185 mmol), KOH (85%, 25 g, 379 mmol), and MeOH (200 mL), cooledto rt in a water bath, was added H₂O slowly. The reaction mixtureobtained was stirred at rt for 1.5 h and then concentrated under reducedpressure to remove MeOH. A minimal amount of H₂O was added to theresidue to make a clear solution that was then acidified to pH=1 at 0°C. with aqueous HCl (concentrated HCl, 11 mL; 5N HCl, 10 mL, Then 2N and1N HCl). After heating on a steam bath, the mixture was cooled. Thesolid was filtered, washed with H₂O, and dried under vacuum to givecompound 777B (29 g, 97%) as a yellow solid. HPLC: 100% at 2.14 min(retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 163 [M+H]⁺.

C. 7-Iodo-pyrazolo[1,5-a]pyridine-4-carboxylic acid (777C)

To a stirred suspension of pyrazolo[1,5-a]pyridine-4-carboxylic acid (29g, 179 mmol) in anhydrous THF (1000 mL) cooled at 0° C. was addedlithium hexamethyldisilazide solution (1M in THF, 200 mL, 200 mmol).After the mixture was stirred at 0° C. for 30 min, additional LHMDSsolution (1M in THF, 320 mL, 320 mmol) was added at −4° C. After themixture was stirred for 10 min, iodine (55 g, 215 mmol) was added inportions. The reaction mixture was stirred at −4° C. for 1.5 h, at rtfor 1 h, and then cooled to 0° C. Aqueous HCl (5N, 40 mL) and NaS₂O₃solution (10 g in 40 mL of H₂O) were added. The mixture was stirred at0° C. for 30 min, and then concentrated under reduced pressure. Theresidual mixture was mixed with sat. NaHCO₃ solution (100 mL), ethylether (150 mL), and H₂O (130 mL). The ether solution was separated andextracted with H₂O (50 mL). The combined aqueous solutions were washedwith ethyl ether (150 mL), acidified to pH=1 with saturated aqueoussolution of KHSO₄, heated in a steam bath, and then cooled. The solidwas filtered, washed with H₂O, and then dried to give compound 777C (50g, 97%) as a yellow solid. HPLC: 100% at 2.88 min (retention time) (YMCS5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 289 [M+H]⁺.

D. (7-Iodo-pyrazolo[1,5-a]pyridin-4-yl)-carbamic acid tert-butyl ester(777D)

To a clear solution of 7-iodo-pyrazolo[1,5-a]pyridine-4-carboxylic acid(23.4 g, 81.2 mmol) and diisopropylethylamine (65 mL) in tert-butanol(250 mL) and anhydrous toluene (200 mL) was added diphenyl phosphorylazide (25 mL, 114 mmol) under argon. After the mixture was stirred at rtfor 30 min, the temperature was raised slowly to 90° C. The mixture wasstirred at 90° C. overnight and concentrated under reduced pressure toremove the solvents. The residue was partitioned between EtOAc (200 mL)and aqueous NaOH solution (2N, 75 mL). The aqueous solution wasseparated and extracted with EtOAc (100 mL). The combined organicsolutions were washed with aqueous NaOH solution (1N, 75 mL), dried overNa₂SO₄, and concentrated under reduced pressure. Purification by silicagel flash chromatography eluting with EtOAc/heptane (gradient from 0:1to 1:1 ratio) gave a brownish solid. Recrystallization in heptane withsome EtOAc gave compound 777D (19.6 g, 67%) as a yellow solid. HPLC: 95%at 3.83 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 360 [M+H]⁺.

E. (7-Cyano-pyrazolo[1,5-a]pyridin-4-yl)-carbamic acid tert-butyl ester(777E)

A mixture of (7-iodo-pyrazolo[1,5-a]pyridin-4-yl)-carbamic acidtert-butyl ester (36 mg, 0.1 mmol), zinc cyanide (24 mg, 0.2 mmol),tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), andanhydrous DMF (1 mL) was degassed with argon. Then, the mixture wasstirred at 80° C. for 4.5 h, cooled to rt, mixed with EtOAc (6 mL), andfiltered. The filtrate was concentrated under reduced pressure.Purification by silica gel flash chromatography eluting withEtOAc/heptane (gradient from 1:4 to 1:2 ratio) gave compound 777E (24mg, 93%) as a white solid. HPLC: 93% at 3.64 min (retention time) (YMCS5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 259 [M+H]⁺.

F. 4-Amino-pyrazolo[1,5-a]pyridine-7-carbonitrile (777F)

To a clear solution of (7-cyano-pyrazolo[1,5-a]pyridin-4-yl)-carbamicacid tert-butyl ester (3 g, 11.6 mmol) in methylene chloride (40 mL) wasadded TFA (8 mL). The mixture was stirred at rt for 3 h, and thenconcentrated under reduced pressure. The residue was partitioned betweenEtOAc (100 mL) and sat. NaHCO₃ solution (50 mL). The aqueous solutionwas separated and extracted with EtOAc (2×50 mL). The combined organicsolutions were dried over Na₂SO₄, filtered though SiO₂ pad, andconcentrated under reduced pressure. Crystallization in EtOAc and 95%EtOH gave compound 777F (1.07 g, 58%) as a dark yellow solid. HPLC: 97%at 1.96 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 159 [M+H]⁺.

G. (777G)

A mixture of 4-amino-pyrazolo[1,5-a]pyridine-7-carbonitrile (135 mg,0.85 mmol), compound 752 (225 mg, 1.06 mmol), 4 Å molecular sieve powder(850 mg), and DMA (0.85 mL) was stirred under argon at rt for 10 min, at170° C. for 3 h, and then cooled to rt. The molecular sieve powder wasfiltered off, and the filtrate was concentrated under reduced pressure.Purification by silica gel flash chromatography eluting with EtOAc(gradient with MeOH from 0% to 5%) gave compound 777G (98 mg, 33%) as ayellowish solid. HPLC: 99% at 2.28 min (retention time) (YMC S5 ODS-Acolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 353 [M+H]⁺. The absolute stereochemistry of compound 777G isestablished by the known stereochemistry of the intermediate compound752 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 778

A mixture of 4-amino-pyrazolo[1,5-a]pyridine-7-carbonitrile (60 mg, 0.38mmol), compound 751 (110 mg, 0.52 mmol), MgSO₄ (360 mg, 3 mmol),diisopropylethylamine (0.35 mL, 2 mmol), and anhydrous toluene (0.6 mL)was stirred at 135° C. under argon for 20 h. Purification by silica gelflash chromatography eluting with EtOAc (gradient with MeOH from 0% to5%) gave compound 778 (115 mg, 86%) as a greyish solid. HPLC: 98% at2.28 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 353 [M+H]⁺. The absolutestereochemistry of compound 778 is established by the knownstereochemistry of the intermediate compound 751 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 779

A clear solution of compound 20A (50 mg, 0.25 mmol), p-aminoacetophenone(68 mg, 0.5 mmol), and N,N-dimethylformamide dimethyl acetal (0.065 mL,0.49 mmol) in anhydrous N,N-dimethylformamide (0.2 mL) was stirred at10° C. under argon for 18 h, and then concentrated. Purification bysilica gel flash chromatography on SiO₂ eluting with EtOAc/heptane(gradient from 1:4 to 1:0 ratio) gave a solid that was crystallized in amixture of EtOAc and heptane to give compound 779 (11 mg, 14%) as awhite solid. HPLC: 98% at 2.89 min (retention time) (YMC S5 ODS-A column4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 314[M+H]⁺.

EXAMPLE 780

A. 1,4-Dimethyl-7-aza-bicyclo[2.2.1]hepta-2,5-diene-2,3,7-tricarboxylicacid 7-tert-butyl ester 2,3-dimethyl ester (780A)

A mixture of crude 2,5-dimethyl-pyrrole-1-carboxylic acid tert-butylester (prepared according to a literature (Haiser, H.-P.; et al. J. Org.Chem. 1984 49(22) 4203-4209); 500 mg) and dimethylacetylenedicarboxylate (0.5 mL, ca 4 eq) was stirred at 120° C. underargon for 2 h. Purification by silica gel flash chromatography on SiO₂eluting with EtOAc/heptane (gradient from 1:20 to 1:2 ratio) gavecompound 780A (166 mg, 50% yield) as a colorless liquid. HPLC: 90% at3.67 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

B. (780B)

To a clear solution of1,4-dimethyl-7-aza-bicyclo[2.2.1]hepta-2,5-diene-2,3,7-tricarboxylicacid 7-tert-butyl ester 2,3-dimethyl ester (1.5 g, 4.4 mmol) in MeOH (10mL) and H₂O (5 mL) cooled in ice water was added KOH (2.9 g, 44 mmol) inportions. More H₂O (5 mL) was then added. After the reaction mixture wasstirred at rt for 1 h, hydrazine (1.4 mL, 44 mmol), HCl (2N aqueoussolution, 17 mL, 34 mmol), and hydrogen peroxide (50% aqueous solution,1.27 mL, 22 mmol) were added sequentially at 0° C. The reaction mixturewas stirred at rt for 3 h, and then concentrated under reduced pressureto remove MeOH. The aqueous solution obtained was acidified to pH=1 withsaturated aqueous solution of KHSO₄ and extracted with EtOAc (3×). Thecombined extracts were dried over Na₂SO₄, and concentrated under reducedpressure to give a yellow solid. The yellow solid above was dissolved inacetic anhydride (15 mL). The solution was stirred at 100° C. for 1 h.Concentration under reduced pressure gave 1.3 g (100%) of compound 780Bas an orange solid.

C. (780C)

A mixture of compound 780B (0.8 g, 2.7 mmol),4-amino-2-trifluoromethylbenzonitrile (0.5 g, 2.7 mmol), MgSO₄ (2.6 g,22 mmol), diisopropylethylamine (2.35 mL, 13.5 mmol), and anhydroustoluene (2.9 mL) was stirred at 135° C. under argon for 15 h. The solidwas filtered and washed with EtOAc. The filtrate was concentrated underreduced pressure. Purification by silica gel flash chromatographyeluting with EtOAc/heptane (gradient from 1:4 to 1:2 ratio) gavecompound 780C (1.03 g, 82%) as a glassy solid. HPLC: 100% at 4.26 min(retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 462.34 [M−H]⁻.

EXAMPLE 781

To a solution of compound 780C (770 mg, 1.66 mmol) in methylene chloride(10 mL) was added trifloroacetic acid (5 mL). The reaction mixture wasstirred at rt for 40 min. The mixture was then concentrated underreduced pressure, basified with sat. NaHCO₃ solution, and extracted withEtOAc (3×). The combined extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to give compound 781 (600 mg, 99%)as an orange solid. HPLC: 100% at 2.55 min (retention time) (YMC S5ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 364 [M+H]⁺.

EXAMPLE 782

To a clear solution of compound 781 (27 mg, 0.074 mmol) andtriethylamine (0.061 mL, 0.44 mmol) in anhydrous methylene chloride (3mL) was added acetyl chloride (0.016 mL, 0.22 mmol) at 0° C. underargon. After the mixture was stirred at 0° C. for 30 min and at rt for30 min, sat. NaHCO₃ solution was added. After the mixture was stirredfor 15 min, the organic solution was separated, dried over Na₂SO₄, andfiltered though a SiO₂ pad that was then rinsed with EtOAc. The filtratewas concentrated under reduced pressure. Crystallization in a mixture ofEtOAc and heptane gave compound 782 (19 mg, 63%) as a white solid. HPLC:99% at 3.56 min (retention time) (YMC S5 ODS-A column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm). MS (ES): m/z 406 [M+H]⁺.

EXAMPLE 783(3aα,4β,7β,7aα)-4-(Octahydro-4,7,8-trimethyl-1,3-dioxo-4,7-imino-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(783)

A mixture of compound 781 (180 mg, 0.5 mmol), formaldehyde (37% aqueoussolution, 0.11 mL, 1.5 mmol), NaHB(OAc)₃ (318 mg, 1.5 mmol), and1,2-dichloroethane (9 mL) was stirred at rt under argon overnight, andthen dried over Na₂SO₄. Purification by silica gel flash chromatographyeluting with EtOAc (gradient with triethylamine from 2% to 10%) gavecompound 783 (160 mg, 84%) as a white solid. HPLC: 100% at 2.46 min(retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 378 [M+H]⁺.

EXAMPLE 784

To a clear solution of compound 781 (20 mg, 0.055 mmol) andtriethylamine (0.04 mL, 0.24 mmol) in anhydrous methylene chloride (1mL) cooled at 0° C. was added methanesulfonyl chloride (0.01 mL, 0.13mmol). After the reaction mixture was stirred at 0° C. for 30 min, sat.NaHCO₃ solution (0.1 mL) was added. The mixture was stirred for 10 min,dried over Na₂CO₃, and filtered though a SiO₂ pad that was then rinsedwith EtOAc. The filtrate was concentrated under reduced pressure.Crystallization in a mixture of EtOAc and heptane gave compound 784 (14mg, 58%) as a white solid. HPLC: 98% at 3.58 min (retention time) (YMCS5 ODSA column 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 440 [M−H]⁻.

EXAMPLE 785

To a stirred solution of compound 230Bi (50 mg, 0.13 mmol) andtriethylamine (0.09 mL, 0.65 mmol) in anhydrous methylene chloride (5mL) was added phosgene (20% in toluene, 0.25 mL, 0.48 mmol) dropwise.After the reaction was completed, sat. NaHCO₃ solution was added. Themixture was extracted with EtOAc (3×). The combined extracts were driedover Na₂SO₄, filtered though a SiO₂ pad, and concentrated under reducedpressure. Crystallization in a mixture of EtOH and H₂O gave compound 785(40 mg, 73%) as a white solid. HPLC: 100% at 3.55 min (retention time)(YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).MS (ES): m/z 377 [M—CO₂—H]⁻.

EXAMPLES 786i & 786ii[3aR-(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dichloro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&[3aR(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dichloro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(786i & 7861i)

To a stirred mixture of compound 230Bi (544 mg, 1.5 mmol), acetone (10mL), acetic acid (2 mL), and brine (2 mL) cooled at 0° C. was addedbleach (5 mL) dropwise. The clear solution obtained was stirred at rtfor 1 h, and then concentrated under reduced pressure. The residualmixture was extracted with EtOAc (3×). The combined extracts were driedover Na₂SO₄, and concentrated under reduced pressure. Purification bysilica gel flash chromatography on SiO₂ eluting with EtOAc/heptane(gradient from 1:9 to 1:2 ratio) gave a white solid that wascrystallized in a mixture of EtOAc and heptane to give 301 mg (46%) ofracemic mixture of compounds 786i & 786ii as a white solid. HPLC: 100%at 4.11 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 395 [M−HCl—H]⁻.

Chiral HPLC separation the racemic mixture gave two enantiomers:compound 786i & compound 786ii.

Chiral HPLC conditions employed for the separation:

Chiral HPLC Condition

Column: CHIRALPAK AD 50 × 500 mm, 20μ Temperature: rt Injection Volume:20 mL Mobile Phase: A: IPA with 0.1% diethylamine B: Heptane withdiethylamine Isocratic, 45% of A, 60 min. Flow Rate: 50 mL/min. UVDetection: 245 nm

Chiral HPLC Conditions Employed for the Analysis:

Chiral HPLC Condition

Column: CHIRALPAK AD 4.6 × 250 mm, 10μ Temperature: 25° C. InjectionVolume: 10 μL Mobile Phase: A: IPA with 0.1% diethylamine B: Heptanewith diethylamine Isocratic, 45% of A, 15 min. Flow Rate: 1 mL/min. UVDetection: 245 nm RT: Compound 786i 10.6 min Compound 786ii 7.0 min

The absolute stereochemistry of compounds 785i & 785ii has not beenestablished. Although each compound represents a single antipode, thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLES 787i & 787ii[3aR-(3aα,4β,5β,6β,7β,7aα)]-4-(Octahydro-5-chloro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&[3aS-(3aα,4β,5β,6β,7β,7aα)]-4-(Octahydro-5-chloro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(787i & 787ii)

To a stirred solution of compound 230Bi (181 mg, 0.5 mmol) in anhydrousmethylene chloride (4 mL) cooled at −78° C. under argon was addedchromyl chloride (0.048 mL, 0.6 mmol) dropwise. After the reactionmixture was stirred at −78° C. for 1 h, the reaction temperature wasraised slowly to rt. The reaction mixture was stirred at rt for 2 h.Sat. NaHCO₃ solution (10 mL) was then added at 0° C. with vigorousstirring. The mixture was extracted with EtOAc (3×). The combinedextracts were dried over Na₂SO₄, and concentrated under reducedpressure. Purification by silica gel flash chromatography on SiO₂eluting with EtOAc/heptane (gradient from 1:4 to 1:0 ratio) gave 98 mg(47%) of racemic mixture of compounds 787i & 787ii as a white solid.HPLC: 100% at 3.32 min (retention time) (YMC S5 ODS-A column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 377[M—HCl—H]⁻.

Chiral HPLC separation of the racemate gave two enantiomers: compound787i & compound 787ii.

Chiral HPLC Conditions Employed for the Separation:

Chiral HPLC Condition

Column: CHIRALCEL OD 50 × 500 mm, 20μ Temperature: rt Injection Volume:20 mL Mobile Phase: A: IPA with 0.1% diethylamine B: Heptane with 0.1%diethylamine Isocratic, 35% of A, 90 min. Flow Rate: 50 mL/min. UVDetection: 245 nm RT: Compound 787i 41 min Compound 787ii 51 min

The absolute stereochemistry of compounds 787i & 787ii has not beenestablished. Although each compound represents a single antipode, thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 788(3aα,4β,5β,6α,7β,7aα)-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(788B)

A.(3aα,4β,5α,6β,7β,7aα)-4-(Octahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(788A)

To a stirred solution of compound 222B (1.49 g, 3 mmol) in anhydrous THF(31 mL) was added borane-methyl sufide complex (0.61 mL, 6.1 mmol)dropwise at rt under argon. After the reaction mixture was stirred at rtfor 1.5 h, EtOH (20 mL) was added slowly at 0° C., followed by phosphatebuffer (pH=7.2, 39 mL), and H₂O₂ (30% aqueous, 12 mL). The mixture wasvigorously stirred at 0° C. for 30 min, at rt for 21 h, and thenconcentrated under reduced pressure at rt to remove THF. The residue waspartitioned between EtOAc (160 mL) and brine (160 mL). The organicsolution was separated, washed with 5% Na₂SO₃ solution (120 mL), driedover Na₂SO₄, and concentrated under reduced pressure. Purification bysilica gel flash chromatography on SiO₂ eluting with EtOAc/heptane(gradient from 1:8 to 1:0 ratio) compound 788A (1.15 g, 75%) as a foamsolid.

B.[3aS-(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(788B)

To a stirred solution of compound 788A (0.67 g, 1.3 mmol) in EtOH (100%,19 mL) was added concentrated HCl (3.7 mL). The mixture was stirred atrt for 21 h, at 40° C. for 3 h, and then concentrated under reducedpressure. Purification by silica gel flash chromatography eluting withEtOAc/heptane (gradient from 1:1 to 1:0 ratio) gave compound 788B (0.47mg, 92%) as a glassy solid. HPLC: 98% at 3.07 min (retention time) (YMCS5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 397 [M+H]⁺. Compound 788B represents a racemic mixture ofantipodes. The nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 789

To a stirred solution of compound 788B (40 mg, 0.1 mmol) andtriethylamine (0.16 mL, 1.1 mmol) in anhydrous methylene chloride (1 mL)was added methanesulfonyl chloride (0.042 mL, 0.54 mmol) at 0° C. underargon. The reaction mixture was stirred at 0° C. for 10 min, and at rtfor 30 min. Purification by silica gel flash chromatography eluting withEtOAc/heptane (gradient from 1:2 to 1:0 ratio) gave compound 789 (50 mg,90%) as a glassy solid. HPLC: 100% at 3.66 min (retention time) (YMC S5ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 575 [M+Na]⁺. Compound 789 represents a racemic mixture ofantipodes. The nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 790

A clear solution of compound 788B (40 mg, 0.1 mmol), pyridine (0.04 mL,0.49 mmol), and methanesulfonyl chloride (0.032 mL, 0.41 mmol) inanhydrous methylene chloride (1 mL) was stirred at rt for 1 day.Purification by preparative HPLC (YMC S5 ODS column 20×100 mm, 20mL/min, monitoring at 245 nm, gradient elution with 10-100% solvent Bover 10 mins. Solvent A: 10% MeOH-90% H₂O-0.1% TFA. Solvent B: 90%MeOH-10% H₂O-0.1% TFA.) gave compound 790 (23 mg, 48%) as a glassysolid. HPLC: 98% at 3.46 min (retention time) (YMC S5 ODS-A column4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 475[M+H]⁺. Compound 790 represents a racemic mixture of antipodes. Thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 791[3aS-(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&[3aR(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(791i &791ii)

Racemic compound 788B (1 g) was separated into its enantiomers by normalphase preparative chiral HPLC (CHIRALPAK OJ 5×50 cm column; eluting with20% MeOH/EtOH (1:1) in heptane (isocratic)+0.1% diethylamine at 50mL/min) to give 296 mg of faster eluting compound 791i (Chiral HPLC:8.92 min; CHIRALPAK OJ 4.6×250 mm column; eluting with 20% MeOH/EtOH(1:1) in heptane+0.1% diethylamine at 1 mL/min); HPLC: 95% at 1.25 min(retention time) (Phenomenex S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min, monitoring at254 nm); MS (ES): m/z 397.37 [M+H]⁺ and 274 mg of the slower eluting791ii (Chiral HPLC: 11.25 min; CHIRALPAK OJ 4.6×250 mm column; elutingwith 20% MeOH/EtOH (1:1) in heptane+0.1% diethylamine at 1 mL/min);HPLC: 95% at 1.25 min (retention time) (Phenomenex S5 ODS column 4.6×50mm eluting with 10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4mL/min, monitoring at 254 nm); MS (ES): m/z 397.43 [M+H]⁺. The absolutestereochemistry of compounds 791i & 791ii has not been established.Although each compound represents a single antipode, the nomenclatureand structure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 792(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid (792B)

A.(3aα,4β,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)tetrahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid (792A)

A mixture of 2,5-dimethyl-3-furoic acid (11.2 g; 80 mmol) and4-(2,5-dihydro-2,5-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(5.32 g; 20 mmol) in 20 mL of THF was heated to 65° C. for 2 h. Aftercooling to rt, the solid residue was slurried in EtOAc and loaded onto a5×30 cm silica gel column packed in hexanes. The column was eluted with2 L of EtOAc, followed by 1.5 L of 1% AcOH/EtOAc. Fractions containingthe desired acrylic acid were concentrated and the residue wasco-evaporated from EtOAc/Heptane (3×100 mL). After dissolving the solidresidue in ˜15 mL of EtOAc, heptane (˜50 mL) was added and the mixturewas concentrated to ˜25 mL volume. The suspension was filtered and thefilter cake was washed with hexane. Removing the solvent in vacuoafforded compound 792A (1.5 g, 16%) as a white powder.

B.(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid (792B)

Compound 792A (220 mg; 0.54 mmol) was hydrogenated at 1 atm. in EtOAc (5mL) over 10% Pd/C (20 mg) for 4 hs. After filtering though Celite, thefiltrate was concentrated and the residue was chromatographed on a2.5×15 cm silica gel column eluting with EtOAc:Heptane, 1:1+0.5% AcOH.Pure fractions were concentrated to afford compound 792B (173 mg, 79%)as a colorless glass. HPLC: 95.7% at 1.64 min (retention time)(Phenomonex S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 2 mincontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES):m/z 409.23 [M+H]⁺.

EXAMPLE 793(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, methyl ester (793B)

A.(3aα,4β,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)tetrahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, methyl ester (793A)

A mixture of methyl-2,5-dimethyl-3-furoate (30 mL; 200 mmol) and4-(2,5-dihydro-2,5-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(13.3 g; 50 mmol) was heated to 120° C. for 5 h. After cooling slowly tort over 18 h, ethyl ether (˜150 mL) was added and the resulting thicksuspension was filtered. Rinsing thoroughly with ethyl ether and dryingafforded compound 793A (11.3 g, 54%) as a white powder.

B.(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, methyl ester (793B)

Compound 793A (1 g; 2.38 mmol) was hydrogenated at 1 atm. in EtOAc (25mL) over 10% Pd/C (100 mg) for 2 h. After filtering though Celite, thefiltrate was concentrated and the residue was chromatographed on a2.5×15 cm silica gel column eluting with EtOAc:Hexane, 1:3. Purefractions were concentrated to afford compound 793B (665 mg, 65%) as ayellow powder. HPLC: 99% at 1.67 min (retention time) (Phenominex S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 2mincontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES): m/z423.27 [M+H]⁺. Compound 793B represents a racemic mixture of antipodes.The nomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 794B

A. (794A)

One drop of DMF was added to a solution of compound 792B (160 mg; 0.4mmol) and oxalyl chloride (0.09 mL; 1 mmol) in methylene chloride (4 mL)at rt. After stirring 1 h at rt, the volatiles were removed in vacuo andthe residue was dissolved in 2 mL of THF to afford a 0.2M solution ofcompound 794A in THF.

C. (794B)

A 0.2M solution of compound 794A in THF (1 mL; 0.2 mmol) was added to a0.5M solution of ammonia in dioxane (5 mL; 2.5 mmol) at rt. Afterstanding 1 h at rt, the reaction mixture was partitioned between EtOAc(25 mL) and water (25 mL). The organic layer was washed with saturatedpotassium bisulfate solution (25 mL) and brine (25 mL). Drying overMgSO₄ followed by concentration in vacuo gave a solid residue that wastriturated with ethyl ether to afford compound 794B (60 mg, 74%) as awhite solid. HPLC: 95.6% at 1.41 min (retention time) (Phenominex S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 2mincontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES): m/z408.03 [M+H]⁺. Compound 794B represents a racemic mixture of antipodes.The nomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 795

A 0.2M solution of compound 794A in THF (1 mL; 0.2 mmol) was added to a2.0M solution of dimethylamine in dioxane (2.5 mL; 5 mmol) at rt. Afterstanding 1 h at rt, the reaction mixture was partitioned between EtOAc(25 mL) and water (25 mL). The organic layer was washed with saturatedpotassium bisulfate solution (25 mL) and brine (25 mL). Drying overMgSO₄ followed by concentration in vacuo gave a residue that waspurified by preparative TLC (EtOAc:Hexane, 3:2) to afford compound 795(45 mg, 52%) as a white powder. HPLC: 99% at 1.52 min (retention time)(Phenominex S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 2 mincontaining 0.1% TFA, 4 mL/min, monitoring at 2541m); MS (ES):m/z 435.10 [M+H]⁺. Compound 795 represents a racemic mixture ofantipodes. The nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 796[3aR-(3aα,4β,7β,7aα)]-4-(Octahydro-4,7-dimethyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(796)

Compound 471Di (0.10 g, 0.263 mmol) was dissolved in a mixture of CH₂Cl₂(1.0 mL) and THF (2.0 mL) at 22° C. Dess-Martin periodinane (0.279 g,0.658 mmol) was added with stirring. After 3 h, the reaction wasquenched with a 1:1 mixture of sat aq NaHCO₃ and sat aq NaHSO₃ (5 mL).After stirring for 15 min, the mixture was extracted with CH₂Cl₂ (3×10mL) and the combined organics were dried over Na₂SO₄. The crude materialwas purified by silica gel flash chromatography eluting with 5-10-20%acetone in chloroform to give compound 796 (0.090 g) as a white solid.HPLC: 100% at 3.170 min (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ES): m/z 379.11[M+H]⁺. Chiral analytical HPLC using a Chiracel OD column, 4.6×250 mm,eluting with 20% (1:1) EtOH/MeOH in hexanes at 2.0 mL/min and monitoringat 220 nm gave a retention time of 9.097 mins. The absolutestereochemistry of compound 796 is established by the knownstereochemistry of the intermediate compound 741Di and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 797[3aS-(3aα,4β,7β,7aα)]-4-(Octahydro-4,7-dimethyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(797)

Compound 471Dii (0.10 g, 0.263 mmol) was dissolved in a mixture ofCH₂Cl₂ (1.0 mL) and THF (2.0 mL) at 22° C. Dess-Martin periodinane(0.279 g, 0.658 mmol) was added with stirring. After 3 h, the reactionwas quenched with a 1:1 mixture of sat aq NaHCO₃ and sat aq NaHSO₃ (5mL). After stirring for 15 min, the mixture was extracted with CH₂Cl₂(3×10 mL) and the combined organics were dried over Na₂SO₄. The crudematerial was purified by silica gel flash chromatography on SiO₂ elutingwith 5-10-20% acetone in chloroform to give compound 797 (0.094 g) as awhite solid. HPLC: 100% at 3.170 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ES): m/z 379.11[M+H]⁺. Chiral analytical HPLC using a Chiracel OD column, 4.6×250 mm,eluting with 20% (1:1) EtOH/MeOH in hexanes at 2.0 mL/min and monitoringat 220 nm gave a retention time of 5.710 mins. The absolutestereochemistry of compound 797 is established by the knownstereochemistry of the intermediate compound 471Dii and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 798[3aR-(3aα,4β,7β,7aα)]-4-[5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]tetrahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile&[3aR-(3aα,4β,7β,7aα)]-4-[5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]tetrahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile(798i and 798ii)

The individual enantiomers of compound 222B were separated bypreparativechiral HPLC using a Chiracel OD column, 50×500 mm, elutingwith 12% EtOH in hexanes at 50 mL/min and monitoring at 220 nm. Compound798i has a retention time of 22 min(>99% ee by analytical) and Compound798ii had a retention time of 40 min(95% ee by analytical). Absolutestereochemistry was confirmed by acid hydrolysis of the silyl enol etherto the corresponding ketone (compounds 796 & 797). Comparison by chiralanalytical HPLC clearly demonstrated that the ketone product derivedfrom compound 798i had an identical retention time to that seen forcompound 796 and the ketone product derived from compound 798ii had anidentical retention time to that seen for compound 797. In this fashion,the absolute configuration of compounds 798i & 798ii can be inferred bythe known absolute configuration of compounds 796 & 797. Compound 798i:HPLC: 100% at 4.211 min (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). Compound 798ii: HPLC:100% at 4.210 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm).

EXAMPLE 799[3aS-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(799)

Compound 798i (2.20 g, 4.47 mmol) was dissolved in acetonitrile (45 mL)and cooled to 0° C. 1-Fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octanebis-(tetrafluoroborate) (50% w/w on alumina, 5.75 g, 8.94 mmol) was thenadded with vigorous stirring. After 0.5 h, the reaction was quenchedwith sat aq NaHCO₃ (20 mL) and brine (20 mL). The resulting mixture wasextracted with EtOAc (3×50 mL). The combined organics were dried overanhydrous MgSO₄ and concentrated in vacuo. The crude material waspurified by silica gel flash chromatography on SiO₂ eluting with 0-35%acetone in chloroform to give a mixture of ketone and hydrate. Themixture was dissolved in CH₃CN (50 mL) and water (5.0 mL) was added. Themixture was stirred for 3 h and then concentrated in vacuo followed byazeotroping with additional CH₃CN three times and then dried in vacuo at50° C. for 12 h to give compound 799 (1.09 g) as a white solid. Compound799 was shown to be the hydrate only by ¹H and ¹⁹F NMR spectroscopy.HPLC: 100% at 2.687 min (retention time) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ES): m/z 413.27[M−H]⁺. The absolute stereochemistry of compound 799 is established bythe known stereochemistry of the intermediate compound 798i and theretention of configuration therein. The absolute stereochemistry is asdrawn in the above FIGURE and rendered by the nomenclature.

EXAMPLE 800[3aS-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&[3aR(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(799Ci and 799Cii)

A. (800A)

2-Methyl furan (5.33 mL, 59.1 mmol) was added to4-(2,5-dioxo-2,5-dihydropyrrol-1-yl)-2-trifluoromethylbenzonitrile (1.50g, 5.91 mmol) and the mixture was heated at 60° C. for 3 h. Uponheating, the reaction became homogenous followed shortly by the productcrashing out of solution. The mixture was cooled to 22° C. and dilutedwith heptane (25 mL) and filtered, rinsing with cold heptane.Concentration in vacuo gave compound 800A (1.76 g) as a white solid.This compound was taken forward without further purification. HPLC: 100%at 2.250 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

B.(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(800B)

Compound 800A (0.500 g, 1.49 mmol) was dissolved in dry THF (15 mL) andWilkinson's catalyst (0.028 g, 0.029 mmol) was added. After stirring for10 min, catecholborane (1.0 M soln in THF, 3.00 mL, 3.00 mmol) was thenadded over a 5 min period. After 1 h, the reaction was cooled to 0° C.followed by sequential addition of EtOH (7.0 mL), pH 7.4 phosphatebuffer (16.0 mL) and 30% aq H₂O₂ (1.5 g). The mixture was slowly warmedto 22° C. and after 2 h, extracted with CH₂Cl₂ (3×50 mL). The combinedorganics were washed once with a 1:1 mixture of 1N NaOH/sat aq NaHSO₃(50 mL), once with brine and dried over anhydrous Na₂SO₃. The crudematerial was purified by silica gel flash chromatography on SiO₂ elutingwith 5-10-20-40% acetone in chloroform to give compound 800B (0.344 g)as a white foam. NMR spectroscopy confirmed assignment and no otherisomers were present. HPLC: 94% at 2.460 min (retention time) (YMC S5ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm), MS(ES): m/z 367.22 [M+H]⁺.

C.[3aS-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile&[3aR-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(800Ci & 800Cii)

The individual enantiomers of compound 800B were separated bypreparative chiral HPLC using a Chiralcel OD column (50×500 mm) elutingwith 17% EtOH/hexanes at 50 mL/min monitoring at 220 nm. Compound 800Cihas a retention time of 69.4 min and compound 800Cii has a retentiontime of 84.1 min. Absolute stereochemistry was not determined. Compound800Ci: HPLC: 100% at 2.460 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). Compound 800Cii: HPLC:100% at 2.460 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm). The absolute stereochemistry ofcompounds 800Ci & 800Cii has not been established. Although eachcompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 801[3aR-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-3-iodophenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(801C)

A. 1-Chloro-2-iodo-4-nitro-benzene (801A)

2-amino-5-nitro-iodobenzene (10.00 g, 37.9 mmol) was suspended in 12 NHCl (25 mL) and water (40 mL) and stirred for 30 min at 22° C. Themixture was then cooled to 0° C. and NaNO₂ (5.23 g, 75.8 mmol in 18 mLof H₂O) was added over a 10 min period. After 1 h, this solution wastransferred to a solution of CuCl (3.75 g, 37.9 mmol) in water (50 mL)at 60° C. After 2 h, the mixture was cooled to 22° C. and extracted withEtOAc (3×150 mL) and the organics were dried over anhydrous MgSO₄. Thecrude product was purified by silica gel flash chromatography elutingwith 10-20% CH₂Cl₂ in hexanes to give compound 801A (4.20 g) as a yellowsolid. HPLC: 100% at 3.447 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm).

B. 4-Chloro-3-iodo-phenylamine (801B)

1-Chloro-2-iodo-4-nitro-benzene (2.00 g, 7.09 mmol) was dissolved in THF(30 mL) at 60° C. and EtOH (35 mL) was added followed by NH₄Cl (0.569 g,10.6 mmol in 30 mL of water) and iron powder (1.58 g, 28.4 mmol). Thismixture was stirred vigorously for 3 h and then cooled in 22° C. andfiltered though celite rinsing with EtOAc. The solution was thenconcentrated to 30 mL in vacuo and then poured into a 1:1 solution of 1NNaOH/brine (100 mL). This mixture was then extracted with EtOAc (3×50mL) and the organics were dried over anhydrous MgSO₄. Filtration andconcentration gave compound 801B as a yellow solid. No purification wasnecessary. HPLC: 100% at 2.310 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ES): m/z 517.6[M+Na]⁺.

C.[3aR-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-3-iodophenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(801C)

Compound 801B (0.300 g, 1.19 mmol) and compound 752 (0.229 g, 1.08 mmol)were added to DMA (1.2 mL) in a high pressure reaction vessel. 4Amolecular seives (0.300 g) were then added and the vessel sealed andheated to 190° C. After 45 min, the reaction was cooled to rt and pouredinto EtOAc (50 mL). The solution was then washed once with water (20mL), three times with sat aq NH₄Cl (20 mL) and dried over anhydrousMgSO₄. The crude material was purified by flash chromatography on silicaeluting with 10-20-30% acetone in chloroform to give compound 801C(0.217 g) as a tan solid. HPLC: 100% at 3.000 min (retention time) (YMCS5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm), MS(ES): m/z 448.18 [M+H]⁺. The absolute stereochemistry of compound 801Cis established by the known stereochemistry of the intermediate compound752 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 802

A. (802A)

4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(0.200 g, 0.79 mmol) and 2-(N,N-dimethylaminomethyl)-5-methylfuran(0.548 g, 3.94 mmol) were dissolved in THF (0.5 mL) and heated to 60° C.for 3 h. The mixture was then concentrated in vacuo to give compound802A as a brown oil. The crude material was used without purification.

B. (802B)

Compound 802A (˜0.4 mmol) was dissolved in EtOAc (5.0 mL) and Pd/C (10%Pd, 0.020 g) was added followed by introduction of H₂ via a balloon.After 3 h, the reaction was purged with N₂ and filtered through celiterinsing with EtOAc. The crude material was purified by silica gel flashchromatography eluting with 10-20-30% acetone in chloroform to givecompound 802B (0.080 g) as a tan oil. HPLC: 95% at 2.040 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm), MS (ES): m/z 408.31 [M+H]⁺. Compound 802B represents a racemicmixture of antipodes. The nomenclature and structure shown does notreflect the absolute stereochemistry of the compound.

EXAMPLE 803

A. 2,5-Dimethylfuran-3-carboxylic Acid 2-Methoxyethoxymethyl Ester(803A)

A 2 L round-bottomed flask equipped with a mechanical stirrer wascharged with 2,5-dimethyl-3-furoic acid (81.0 g, 0.58 mol) and potassiumcarbonate (95.9 g, 0.69 mol) in DMF (500 mL). An ice bath was used tocool the reaction as 2-methoxyethoxymethyl chloride (72.2 g, 0.58 mol)was added portionwise. The reaction was stirred for 5 h at rt. Themixture was then diluted with water (1.5 L) and extracted with EtOAc(2×600 mL). The combined organics were washed with water (2×900 mL) andsaturated sodium chloride solution (1 L), dried over MgSO₄, filtered andconcentrated to afford compound 803A (103 g, 82%) as a yellow oil. ¹HNMR (CDCl₃): δ=6.23 (s, 1H), 5.47 (s, 1H), 3.84 (m, 2H), 3.56 (m, 2H),3.38 (s, 3H), 2.51 (s, 3H) and 2.20 ppm (s, 3H).

B. (803B)

A 250 mL round-bottomed flask was charged with4-(2,5-dioxo-2,5-dihydropyrrol-1-yl)-2-trifluoromethylbenzonitrile (15.0g, 0.056 mol) and 2,5-dimethylfuran-3-carboxylic acid2-methoxyethoxymethyl ester (22.8 g, 0.10 mol). The mixture was heatedto 125° C. for 1.5 h then stirred at rt overnight. The crude product wasdissolved in EtOAc and adsorbed onto silica gel. Purification by silicagel chromatography, eluting with 30% EtOAc in hexanes, afforded compound803B (8.21 g, 30%) as a viscous oil. ¹H NMR (CDCl₃): δ=7.95 (d, J=8.3Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.75 (m, 1H), 7.13 (s, 1H), 5.44 (m,2H), 3.83 (m, 2H), 3.57 (m, 2H), 3.39 (s, 3H), 3.19 (d, J=6.5 Hz, 1H),3.09 (d, J=6.5 Hz, 1H), 2.04 (s, 3H) and 1.91 ppm (s, 3H).

C. (803C)

A 250 mL Parr hydrogenation bottle was charged with compound 803B (7.75g, 0.015 mol), EtOAc (80 mL) and palladium on carbon (0.40 g, 10% Pd,50% wet). The bottle was placed on a Parr hydrogenation apparatus,pressurized with hydrogen to 5 psi, and shook until the uptake ofhydrogen ceased. Filtration of the contents over celite andconcentration afforded a yellow oil. Purification by silica gelchromatography, eluting with 30% EtOAc in hexanes, afforded compound803C (3.92 g, 50%) as a white solid. HPLC: 100% at 14.5 min (retentiontime) (Hypersil C18 BDS column, 250×4.6 mm, 5 μm, a detection wavelengthof 254 nm, and a flow rate of 1 mL/min. A linear gradient of 90% of 0.1%trifluoroacetic acid in water, 10% acetonitrile (start) to 100%acetonitrile over 15 min, then 100% acetonitrile for 5 min was used).R_(f)=0.61 (SiO₂, 60% EtOAc in hexanes). Mpt>300° C. ¹H NMR (CDCl₃):δ=7.94 (d, J=8.3 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.74 (m, 1H), 5.46 (d,J=6.1 Hz, 1H), 5.34 (d, J=6.1 Hz, 2H), 3.85 (m, 2H), 3.57 (t, J=4.5 Hz,2H), 3.38 (s, 3H), 3.33 (d, J=7.2 Hz, 1H), 3.19 (d, J=7.2 Hz, 1H), 3.04(m, 1H), 2.28 (m, 1H), 2.05 (t, J=12.2 Hz, 1H), 1.78 (s, 3H) and 1.64ppm (s, 3H). m/z=496 [M+H]⁺.

D. (803Di and 803Dii)

Racemic compound 803C was separated into its two enantiomers bypreparative chiral HPLC using a Chiracel OD column (50×500 mm) elutingwith 50% EtOH in Heptane at 100 mL/min and 290 nm detection. Compound803Di had a retention time of 6.68 min and [α]₂₅ ^(D)=+28.7° (c=1.0,MeOH). Compound 803Dii had a retention time of 13.9 min and [α]₂₅^(D)=−29.2° (c=1.0, MeOH). The absolute stereochemistry of compounds803Di & 803Dii has not been established. Although each compoundrepresents a single antipode, the nomenclature and structure shown doesnot reflect the absolute stereochemistry of the compound.

EXAMPLE 804[3aR-(3aα,4β,5α,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid (804)

A 250 mL round-bottomed flask was charged with compound 803Di (9.85 g,19.8 mmol) and THF (60 mL). A solution of 3N hydrochloric acid (50 mL)was added and the reaction mixture stirred for 16 h at rt. Water (60 mL)was then added and the aqueous layer extracted with EtOAc (3×120 mL).The combined organics were dried over sodium sulfate, filtered andconcentrated to afford compound 804 (8.00 g, 98%) which was shown to beidentical to compound 791. HPLC: 100% at 13.3 min (retention time)(Hypersil C18 BDS column, 250×4.6 mm, 5 μm, a detection wavelength of254 nm, and a flow rate of 1 mL/min. A linear gradient of 90% of 0.1%trifluoroacetic acid in water, 10% acetonitrile (start) to 100%acetonitrile over 15 min, then 100% acetonitrile for 5 min was used), MS(ES): m/Z 409 [M+H]⁺. R_(f)=0.41 (SiO₂, 10% MeOH in CH₂Cl₂). Mpt>300° C.[α]₂₅ ^(D)=−28.50 (c=1.0, MeOH). ¹H NMR (CD₃OD): δ=8.12 (d, J=8.3 Hz,1H), 7.92 (s, 1H), 7.82 (dd, J=8.3 and 2.0 Hz, 1H), 3.39 (t, J=6.7 Hz,1H), 3.30 (d, J=6.7 Hz, 1H), 3.00 (dd, J=12.0 and 5.2 Hz, 1H), 2.23 (dd,J=12.0 and 5.2 Hz, 1H), 2.01 (t, J=12.0 Hz, 1H), 1.70 (s, 3H) and 1.57ppm (s, 3H). The absolute stereochemistry of compound 804 has not beenestablished. Although the compound represent a single antipode thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 805[3S-(3aα,4β,5α,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid (805)

Compound 805 was prepared in identical fashion as described in example804 with the exception that compound 803Dii was the starting material inplace of compound 803Di. Compound 805 was obtained in 98% yield. [α]²⁵_(D)=+28.0° (c=1.0, MeOH). The absolute stereochemistry of compound 805has not been established. Although the compound represent a singleantipode the nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 806

A 50 mL round-bottomed flask was charged with dioxane (6 mL), compound804 (400 mg, 0.984 mmol), diphenylphosphoryl azide (334 mg, 1.21 mmol),triethylamine (123 mg, 1.22 mmol) and powdered 4 Å molecular sieves (400mg). The resulting suspension was heated at 50° C. for 1.5 h, thetemperature was then raised to 75° C. and 2-(trimethylsilyl)ethanol (590mg, 5.02 mmol) was added. Heating was continued for an additional 1.5 h.The reaction mixture was then cooled, filtered though a celite pad andthe filtrate concentrated under reduced pressure. Purification of theresidue by silica gel chromatography, eluting with 20% then 40% EtOAc inhexanes, afforded compound 806 (400 mg, 78%) as a white solid. HPLC:100% at 15.3 min (retention time) (Hypersil C18 BDS column, 250×4.6 mm,5 μm, a detection wavelength of 254 nm, and a flow rate of 1 mL/min. Alinear gradient of 90% of 0.1% trifluoroacetic acid in water, 10%acetonitrile (start) to 100% acetonitrile over 15 min, then 100%acetonitrile for 5 min was used), MS (ES): m/z 524 [M+H]⁺. R_(f)=0.79(SiO₂, 50% EtOAc in hexanes). Mpt>300° C. [α]₂₅ ^(D)=−1.8° (c=1.0,MeOH). ¹H NMR (CDCl₃): δ=7.96 (d, J=8.3 Hz, 1H), 7.83 (s, 1H), 7.73 (dd,J=8.3 and 2.0 Hz, 1H), 4.72 (bs, 1H), 4.19 (t, J=12.0 Hz, 2H), 4.05 (m,1H), 3.45 (d, J=8.3 Hz, 1H), 3.12 (d, J=8.3 Hz, 1H), 2.36 (t, J=12.0 Hz,1H), 1.61 (s, 6H), 1.04 (t, J=12.0 Hz, 2H) and 0.05 ppm (s, 6H). Theabsolute stereochemistry of compound 806 has not been established.Although the compound represents a single antipode, the nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 807

Compound 807 was prepared in identical fashion as described in example806 with the exception that compound 805 was the starting material inplace of compound 804. Compound 807 was obtained in 80% yield. [α]²⁵_(D)=+ 1.10 (c=1.0, MeOH). The absolute stereochemistry of compound 807has not been established. Although the compound represents a singleantipode, the nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 808[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-amino-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(808)

A solution of compound 806 (400 mg, 0.76 mmol) in methylene chloride (10mL) was treated with trifluoroacetic acid (2 mL) and the mixture stirredat rt for 2 h. After this time the reaction was rendered basic (pH=9) bythe addition of saturated aqueous sodium carbonate solution (20 mL) andsolid potassium carbonate. The organic phase was then separated and theaqueous layer extracted with methylene chloride (3×40 mL). The combinedorganics were dried over sodium sulfate, filtered, and concentrated toafford compound 808 (283 mg, 99%) as a white solid. HPLC: 100% at 10.5min (retention time) (Hypersil C18 BDS column, 250×4.6 mm, 5 μm, adetection wavelength of 254 nm, and a flow rate of 1 mL/min. A lineargradient of 90% of 0.1% trifluoroacetic acid in water, 10% acetonitrile(start) to 100% acetonitrile over 15 min, then 100% acetonitrile for 5min was used), MS (ES): m/z 380 [M+H]⁺. R_(f)=0.59 (SiO₂, 5% MeOH inCH₂Cl₂). [α]₂₅ ^(D)=−26.7° (c=1.0, MeOH). Mpt=150-152° C. ¹H NMR(CD₃OD): δ=8.12 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 7.83 (dd, J=8.3 and 2.0Hz, 1H), 3.66 (d, J=7.2 Hz, 1H), 3.21 (m, 4H), 2.16 (t, J=12.0 Hz, 1H),1.51 (s, 3H), 1.49 (s, 3H) and 1.42 ppm (dd, J=12.0 and 5.0 Hz, 1H). Theabsolute stereochemistry of compound 808 has not been established.Although the compound represents a single antipode, the nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 809[3aS-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-amino-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(809)

Compound 809 was prepared in identical fashion as described in example808 with the exception that compound 807 was the starting material inplace of compound 806. Compound 809 was isolated in 94% overall yield.[α]²⁵ _(D)=+27.3° (c=1.0, MeOH). The absolute stereochemistry ofcompound 809 has not been established. Although the compound representsa single antipode, the nomenclature and structure shown does not reflectthe absolute stereochemistry of the compound.

EXAMPLE 810(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-ethylsulfonamido-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(810)

A 25 mL round-bottomed flask was charged with a racemic mixture ofcompounds 808 & 809 (102 mg, 0.27 mmol) and methylene chloride (10 mL).Ethanesulfonyl chloride (54.3 mg, 0.42 mmol) and triethylamine (43.6 mg,0.43 mmol) were added and the resulting mixture stirred at rt overnight.Analysis of the reaction mixture by TLC (SiO₂, EtOAc) indicated thepresence of starting material so an additional equivalent ofethanesulfonyl chloride (54.3 mg, 0.42 mmol) was added and stirringcontinued at rt for 4 h. The reaction mixture was then diluted withCH₂Cl₂ (25 mL) and washed with water (10 mL). Drying over magnesiumsulfate, filtration, and concentration afforded a yellow oil.Purification of this oil by silica gel chromatography, eluting with 25%EtOAc in hexanes, then 50% EtOAc in hexanes and finally EtOAc, affordedcompound 810 (55.9 mg, 44%). as a white solid. HPLC: 100% at 13.8 min(retention time) (Hypersil C18 BDS column, 250×4.6 mm, 5 μm, a detectionwavelength of 254 nm, and a flow rate of 1 mL/min. A linear gradient of90% of 0.1% trifluoroacetic acid in water, 10% acetonitrile (start) to100% acetonitrile over 15 min, then 100% acetonitrile for 5 min wasused), MS (ES): m/z 472 [M+H]⁺. R_(f)=0.72 (EtOAc). Mpt=189-192° C. ¹HNMR (CDCl₃): δ=7.94 (d, J=−8.3 Hz, 1H), 7.85 (s, 1H), 7.74 (dd, J=8.3and 2.0 Hz, 1H), 5.72 (d, J=8.3 Hz, 1H), 3.71 (m, 1H), 3.51 (d, J=7.2Hz, 1H), 3.18 (d, J=7.2 Hz, 1H), 3.11 (q, J=7.2 Hz, 2H), 2.37 (t, J=12.0Hz, 1H), 1.67 (m, 1H), 1.62 (s, 3H), 1.61 (s, 3H) and 1.40 ppm (t, J=7.2Hz, 3H). The absolute stereochemistry of compound 810 has not beenestablished. Although the compound represents a single antipode, thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 811(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[r((phenylmethyl)amino)carbonyl]oxy]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(811)

A 25 mL round-bottomed flask was charged with compound 222D (102 mg,0.27 mmol) and THF (2 mL). Benzyl isocyanate (37.7 mg, 0.28 mmol) wasadded and the resulting mixture stirred at rt for 1.5 h then heated at60° C. for an additional 1.5 h. Sodium hydride (50 mg, 60% dispersion inmineral oil) was then added followed by additional benzyl isocyanate(37.7 mg, 0.28 mmol). Heating was continued at 60° C. overnight. Benzylisocyanate (75.4 mg, 0.56 mmol) and THF (2 mL) were then added and thereaction re-heated to 60° C. for an additional 3 h. The reaction mixturewas then cooled to rt and concentrated under reduced pressure to affordan off white solid. Ether (20 mL) was then added and a precipitateformed. The mixture was filtered and the filtrate concentrated to awhite solid, which was further purified by preparative HPLC. Fractionscontaining the desired product were concentrated and a solution ofsaturated sodium bicarbonate (15 mL) added. The aqueous layer wasextracted with methylene chloride (3×25 mL), dried over magnesiumsulfate, filtered, and concentrated to afford compound 811 (119 mg, 80%)as a white solid. HPLC: 100% at 15.3 min (retention time) (Hypersil C18BDS column, 250×4.6 mm, 5 μm, a detection wavelength of 254 nm, and aflow rate of 1 mL/min. A linear gradient of 90% of 0.1% trifluoroaceticacid in water, 10% acetonitrile (start) to 100% acetonitrile over 15min, then 100% acetonitrile for 5 min was used), MS (ES): m/z 514[M+H]⁺. R_(f)=0.58 (SiO₂, 50% EtOAc in hexanes). Mpt>300° C. ¹H NMR(CDCl₃): δ=7.94 (d, J=8.1 Hz, 1H), 7.85 (s, 1H), 7.74 (m, 1H), 7.36-7.34(m, 5H), 5.07 (bs, 1H), 4.92 (m, 1H), 4.39 (bs, 2H), 3.59 (m, 1H), 3.11(m, 1H), 2.35 (t, J=12.0 Hz, 1H) and 1.61 ppm (s, 6H). The absolutestereochemistry of compound 811 has not been established. Although thecompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 812[3aR-(3aα,4β,5α,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-N-methyl-N-phenyl-1H-isoindole-5-carboxamide(812)

To a dry, nitrogen purged 100 mL round-bottomed flask was added compound804 (100 mg, 0.245 mmol) and CH₂Cl₂ (10 mL). The solution was stirred atrt and oxalyl chloride (311 mg, 2.45 mmol) and N,N-dimethylformamide(28.0 mg, 0.387 mmol) were added. Gas evolution was observed and thereaction was stirred at rt for 1 h. The resulting solution was thenconcentrated to dryness under reduced pressure and CH₂Cl₂ (10 mL) wasadded. N-Methylaniline (262 mg, 2.45 mmol) was added and the reactionstirred for 15 h at rt. After concentrating the resulting solution underreduced pressure, the resulting oil was chromatographed on silica gel,using 50% EtOAc in hexanes as the eluant, to give an orange oil that wascontaminated with N-methylaniline. The material was re-chromatographedon silica gel, using 40% EtOAc in hexanes as eluant, to afford compound812 (115 mg, 94%) as a white foam. HPLC: 100% at 18.7 min (retentiontime) (Hypersil C18 BDS column, 250×4.6 mm, 5 μm, a detection wavelengthof 254 nm, and a flow rate of 1 mL/min. A linear gradient of 90% of 0.1%trifluoroacetic acid in water, 10% acetonitrile (start) to 100%acetonitrile over 15 min, then 100% acetonitrile for 5 min was used), MS(ES): m/z 498 [M+H]⁺. R_(f)=0.37 (SiO₂, 40% EtOAc in hexanes). Mpt>300°C. [α]²⁵ _(D)=−30.0° (c=1.0, MeOH). ¹H NMR (CDCl₃): δ=7.92 (d, J=8.4 Hz,1H), 7.84 (d, J=1.5 Hz, 1H), 7.73 (dd, J=8.3 and 2.0 Hz, 1H), 7.52-7.35(m, 3H), 7.17 (d, J=7.1 Hz, 2H), 4.24 (d, J=7.3 Hz, 1H), 3.30 (s, 3H),3.28 (d, J=7.3 Hz, 1H), 3.09-2.96 (m, 1H), 2.10-1.99 (m, 1H), 1.81 (t,J=12.0 Hz, 1H), 1.56 (s, 3H) and 1.41 ppm (s, 3H). The absolutestereochemistry of compound 812 has not been established. Although thecompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 813

A 25 mL round-bottomed flask was charged with dioxane (3 mL), compound805 (76.3 mg, 0.187 mmol), diphenylphosphoryl azide (62.6 mg, 0.227mmol), triethylamine (23.2 mg, 0.230 mmol) and powdered 4 Å molecularsieves (200 mg) and the resulting suspension heated at 50° C. for 1.5 h.The temperature was then raised to 75° C. and phenol (93.0 mg, 0.988mmol) added. Heating was continued for an additional 1.5 h. The reactionmixture was then cooled, filtered though a celite pad and the filtrateconcentrated under reduced pressure. Purification of the residue bysilica gel chromatography, eluting with 10%-50% EtOAc in hexanes,afforded compound 813 (71.5 mg, 77%) as a white solid. HPLC: 100% at15.9 min (retention time) (Hypersil C18 BDS column, 250×4.6 mm, 5 μm, adetection wavelength of 254 nm, and a flow rate of 1 mL/min. A lineargradient of 90% of 0.1% trifluoroacetic acid in water, 10% acetonitrile(start) to 100% acetonitrile over 15 min, then 100% acetonitrile for 5min was used), R_(f) 0.70 (SiO₂, 50% EtOAc in hexanes). [α]₂₅ ^(D)=+13.0° (c=1.0, MeOH). Mpt>300° C. HPLC: R_(t)=15.9 min. ¹H NMR (CD₃OD):δ=8.14 (d, J=8.3 Hz, 1H), 7.95 (s, 1H), 7.85 (dd, J=8.3 and 2.0 Hz, 1H),7.41-7.12 (m, 5H), 4.06 (dd, J=12.0 and 5.0 Hz, 1H), 3.55 (d, J=7.2 Hz,1H), 3.29 (d, J=7.2 Hz, 1H), 2.29 (t, J=12.0 Hz, 1H), 1.71 (dd, J=12.0and 5.0 Hz, 1H), 1.56 (s, 3H) and 1.54 ppm (s, 3H). The absolutestereochemistry of compound 813 has not been established. Although thecompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 814

Compound 814 was prepared in identical fashion as described in example813 with the exception that compound 804 was the starting material inplace of compound 805. Compound 814 was isolated in 62% overall yield.[α]²⁵ _(D)=−11.7° (c=1.0, MeOH). The absolute stereochemistry ofcompound 814 has not been established. Although the compound representsa single antipode, the nomenclature and structure shown does not reflectthe absolute stereochemistry of the compound.

EXAMPLE 815

Compound 807 (0.060 g, 0.15 mmol) was dissolved in 2 mL of CH₂Cl₂ andtriethylamine (0.020 g, 0.16 mmol) and a catalytic amount of DMAP wereadded followed by isobutyryl chloride (0.02 g, 0.16 mmol). The reactionwas stirred for 1 h at 23° C. when HPLC showed complete consumption ofstarting material. The reaction was diluted with CH₂Cl₂, washedsuccessively with 1N HCl, saturated sodium bicarbonate, brine, dried(MgSO₄), filtered and concentrated in vacuo to give compound 815 (0.06g, 83%), as a white solid. No was purification necessary. HPLC: 100% at3.12 min(YMC S5 ODS column) eluting with 10-90% aqueous methanolcontaining 0.2% phosphoric acid over a 4 min gradient monitoring at 220nm. LC/MS—[M+H]=450.12. The absolute stereochemistry of compound 815 hasnot been established. Although the compound represents a singleantipode, the nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 816[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[[(cyclopropylmethyl)amino]carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(816)

A 50 mL round-bottomed was charged with compound 815 (0.052 g, 0.10mmol), methyl sulfoxide (2 mL) and aminomethylcyclopropane (10 μL, 8.2mg, 0.11 mmol). The reaction was stirred for 4 h after which time thereaction mixture was diluted with water (9 mL) and saturated NaHCO₃solution (1 mL). Extraction with CH₂Cl₂ (1×20 mL then 1×10 mL), dryingover MgSO₄, filtration and concentration afforded the crude product as ayellow oil. Purification by silica gel chromatography, eluting with 20%to 50% EtOAc in hexanes afforded compound 816 (33.6 mg, 67%). HPLC: 100%at 12.9 min (retention time) (Hypersil C18 BDS column, 250×4.6 mm, 5 μm,a detection wavelength of 254 nm, and a flow rate of 1 mL/min. A lineargradient of 90% of 0.1% trifluoroacetic acid in water, 10% acetonitrile(start) to 100% acetonitrile over 15 min, then 100% acetonitrile for 5min was used), MS (ES): m/z 477 [M+H]⁺. R_(f)=0.42 (SiO₂, 50% EtOAc inhexanes). Mpt>300° C. [α]²⁵ _(D)=−31.5° (c=1.0, MeOH). ¹H NMR (CDCl₃):δ=8.12 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J=8.3 Hz, 1H) 4.12-4.06(m, 1H), 3.46 (d, J=8.3 Hz, 1H), 3.34 (bs, 1H), 3.22 (d, J=8.3 Hz, 1H),1.41 (t, J=12.3 Hz, 1H), 1.54 (s, 3H), 1.50 (s, 3H), 1.01-0.92 (m, 1H),0.51-0.45 (m, 2H) and 0.21-0.17 ppm (m, 2H). The absolutestereochemistry of compound 816 has not been established. Although thecompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 817

A 50 mL round-bottomed was charged with compound 809 (0.057 g, 0.15mmol) and phenyl isocyanate (0.1 mL, 0.9 mmol). After heating for 3 h at65-70° C., analysis of the reaction by HPLC indicated completeconsumption of starting material. Dilution with EtOAc (0.5 mL) andpurification by silica gel chromatography, eluting with 60% EtOAc inhexanes afforded compound 817 (39 mg, 52%) as a white solid. HPLC: 100%at 14.2 min (retention time) (Hypersil C18 BDS column, 250×4.6 mm, 5 μm,a detection wavelength of 254 nm, and a flow rate of 1 mL/min. A lineargradient of 90% of 0.1% trifluoroacetic acid in water, 10% acetonitrile(start) to 100% acetonitrile over 15 min, then 100% acetonitrile for 5min was used), MS (ES): m/z 499 [M+H]⁺. R_(f)=0.17 (50% EtOAc inhexanes). Mpt>300° C. [α]²⁵ _(D)=+30.7° (c=1.0, MeOH). ¹H NMR (CDCl₃):δ=8.12 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.35 (d,J=7.8 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 6.99 (t, J=7.1 Hz, 1H), 4.19-4.14(m, 1H), 3.51 (d, J=7.1 Hz, 1H), 3.27-3.25 (m, 2H), 2.31 (t, J=12.3 Hz,1H), 1.63-1.61 (m, 1H), 1.56 (s, 3H) and 1.55 ppm (s, 3H). The absolutestereochemistry of compound 817 has not been established. Although thecompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 818[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(dimethylamino)sulfonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(817)

A 50 mL round-bottomed flask was charged with compound 808 (100 mg, 0.28mmol), methylene chloride (2 mL), triethylamine (28.3 mg, 0.28 mmol) anddimethylsulfamoyl chloride (40.2 mg, 0.28 mmol). The reaction was thenstirred at rt for 3 h, after which time it was quenched with water (10mL) and extracted with CH₂Cl₂ (2×20 mL). The organic layer was washedonce more with water (10 mL), dried over MgSO₄, filtered andconcentrated to a yellow oil. Purification by silica gel chromatography,eluting with 20% EtOAc in hexanes to 100% EtOAc afforded compound 818(64.2 mg, 47%). HPLC: 100% at 14.2 min (retention time) (Hypersil C18BDS column, 250×4.6 mm, 5 μm, a detection wavelength of 254 nm, and aflow rate of 1 mL/min. A linear gradient of 90% of 0.1% trifluoroaceticacid in water, 10% acetonitrile (start) to 100% acetonitrile over 15min, then 100% acetonitrile for 5 min was used), MS (ES): m/z 487[M+H]⁺. R_(f)=0.19 (SiO₂, 50% EtOAc in hexanes). [α]²⁵ _(D)=−22.8°(c=1.0, MeOH). Mpt=262-269° C. ¹H NMR (CDCl₃): δ=8.12 (d, J=8.3 Hz, 1H),7.94 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 3.61 (m, 1H), 3.54 (d, J=7.2 Hz,1H), 3.35 (s, 1H), 3.22 (d, J=7.2 Hz, 1H), 2.79 (s, 6H), 2.27 (t, J=12.4Hz, 1H), 1.68 (m, 1H), 1.54 (s, 3H) and 1.53 ppm (s, 3H). The absolutestereochemistry of compound 818 has not been established. Although thecompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 819

A mixture of4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-isoquinoline-1-carbonitrile (1 g,4 mmol), 2,5-dimethyl-2,3-dihydrofuran-3-one (0.45 g, 4 mmol), DMAP (20mg, 0.16 mmol), anhydrous methylene chloride (10 mL), and THF (20 mL)was stirred at 80° C. overnight, and then concentrated under reducedpressure. Purification by silica gel flash chromatography on SiO₂eluting with EtOAc/heptane (gradient from 1:4 to 1:0 ratio) gave a solidthat was crystallized in a mixture of EtOAc and heptane to give 0.4 g(28%) of compound 819 as a yellowish solid. HPLC: 90% at 3.37 min(retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 362 [M+H]⁺. Compound 819 representsa racemic mixture of antipodes. The nomenclature and structure showndoes not reflect the absolute stereochemistry of the compound.

EXAMPLE 820

To a stirred solution of compound 819 (36 mg, 0.1 mmol) in anhydrous THF(1 mL) cooled at 0° C. under argon was added MeMgBr (1.4 M THF solution,0.3 mL, 0.4 mmol) dropwise. After the mixture was stirred at 0° C. for 1h and at rt for 10 min, saturated aqueous solution of NH₄Cl was addedwith stirring. The mixture was extracted with EtOAc (3×). The combinedextracts were dried over Na₂SO₄, and concentrated under reducedpressure. Purification by silica gel flash chromatography eluting withEtOAc/heptane (gradient from 1:2 to 1:0 ratio) gave a solid that wascrystallized in a mixture of EtOH and H₂O to give compound 820 (8 mg,21%) as a white solid. HPLC: 97% at 3.36 min (retention time) (YMC S5ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 378 [M+H]⁺. Compound 820 represents a racemic mixture ofantipodes. The nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 821[3aS-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-methyl-2-pyridinecarbonitrile(821)

A mixture of compound 772B (20 mg, 0.14 mmol), compound 751 (48 mg, 0.20mmol) and 4 Å molecular sieves (100 mg) in DMA (0.2 mL) was heated at70° C. in a sealed tube for 5 h. The reaction mixture was filtered andthe residue was washed with EtOAc. The filtrates were combined andwashed with H₂O (2×5 mL) and brine (1×5 mL). The combined aqueous layerswere extracted with EtOAc (2×5 mL) and the combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure. Purificationby silica gel flash chromatography eluting with 30% acetone/CHCl₃ gave55 mg of product contaminated with compound 751. Further purification bysilica gel flash chromatography on SiO₂ eluting with 90% EtOAc/hexanesgave compound 821 (46 mg, 62%) as a white solid. HPLC: 100% at 2.27 min(retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 328.2 [M+H]⁺. The absolutestereochemistry of compound 821 is established by the knownstereochemistry of the intermediate compound 751 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 822 [3aR-(3aα,4β,4aα,5aα,6β,7aα)]-4-(Octahydro-4a-hydroxy-4,6-dimethyl-1,3-dioxo-4,6-epoxycycloprop[f]isoindol-2(1H)-yl)-2-(trifluoromethyl)benzonitrile(822)

A solution of compound 222B (114 mg, 0.231 mmol) in 1,2-dichloroethane(2.30 mL), in a dry flask under argon, was cooled to 0° C. with an icebath. To this solution was added Et₂Zn solution (0.460 mL, 0.462 mmol, 1M in hexanes), followed by dropwise addition of chloroiodomethane (70.0μL, 0.926 mmol). The reaction mixture was stirred at 0° C. for 1 h thenat rt for 18 h. After judging the reaction to be only 50% complete byTLC and HPLC methods, more Et₂Zn (0.469 mL) and chloroiodomethane (70μL) were added and the mixture was stirred at rt for 2.5 h. The reactionmixture was quenched with saturated NH₄Cl, extracted with t-butyl methylether (2×10 mL) and the combined organic layers were dried over MgSO₄and in vacuo. The crude material (174 mg) was dissolved in a mixture ofEtOH (5 mL) and conc. HCl (2 mL) and stirred at rt for 1 h. The mixturewas then diluted with H₂O and extracted with EtOAc (1×25 mL). Theorganic layer was washed with brine (1×25 mL), dried and concentratedunder reduced pressure. Purification by preparative TLC (SiO₂) elutingwith 30% aetone/CHCl₃ gave compound 822 (9.1 mg, 10%) as a tan solid.HPLC: 90% at 3.15 min (retention time) (YMC S5 ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 393.03[M+H]⁺. Compound 822 represents a racemic mixture of antipodes. Thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 823[3′aR-(3′aα,4′β,7′β,7′aα)]-Tetrahydro-4′,7′-dimethyl-2′-[4-cyano-3(trifluoromethyl)phenyl]-spiro[1,3-dioxolane-2,5′-4,7-epoxy(5H)isoindole]-1′,3′(2′H,4′H)-dione(823)

A mixture of compound 796 (44.3 mg, 0.117 mmol), ethylene glycol (0.065mL, 1.17 mmol) and p-toluenesulphonic acid (2.2 mg, 0.012 mmol) inbenzene (3 mL) was refluxed for 18 h. The reaction mixture was thendiluted with benzene, washed with 5% Na₂CO₃ (1×10 mL), H₂O (1×10 mL),dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gelflash chromatography on silica gel eluting with 10% acetone/CHCl₃ gavecompound 823 (44.5 mg, 90%) as a white solid. HPLC: 99% at 3.11 min(retention time) (YMC S5 ODS column, 4.6×50 mm, 10-90% aqueous methanolover 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ESI): m/z 423.01 [M+H]⁺. Compound 823 represents a racemicmixture of antipodes. The nomenclature and structure shown does notreflect the absolute stereochemistry of the compound.

EXAMPLE 824[3′aR-(3′aα,4′β,6′β,7′β,7′aα)]-Tetrahydro-6′-hydroxy-4′,7′-dimethyl-2′-[4-cyano-3(trifluoromethyl)phenyl]-spiro[1,3-dioxolane-2,5′-4,7-epoxy(5H)isoindole]-1′,3′(2′H,4′H)-dione(824B)

A. (824A)

A solution of dimethyldioxirane (32 mL, 1.588 mmol, 0.05 M) was added toa solution of compound 222B (521.6 mg, 1.059 mmol) in acetone (1 mL) atrt. After 2.5 h the reaction was shown to be complete by HPLC and wasconcentrated under reduced pressure to give 559 mg (quant.) of crudecompound 824A as a yellow solid.

B.[3′aR-(3′aα,4′β,6′β,7′β,7′aα)]-Tetrahydro-6′-hydroxy-4′,7′-dimethyl-2′-[4-cyano-3(trifluoromethyl)phenyl]-spiro[1,3-dioxolane-2,5′-4,7-epoxy(5H)isoindole]-1′,3′(2′H,4′H)-dione(824B)

A mixture of compound 824A (57.5 mg, 0.113 mmol), ethylene glycol (0.100mL, 1.13 mmol) and p-toluenesulphonic acid (11.0 mg, 0.057 mmol) inbenzene (5 mL) was refluxed for 18 h. The reaction mixture wasconcentrated in vacuo. Purification by silica gel flash chromatographyeluting with 30% acetone/CHCl₃ gave compound 824B (43 mg, 88%) as awhite solid. HPLC: 98% at 2.87 min (retention time) (YMC S5 ODS column,4.6×50 mm, 10-90% aqueous methanol over 4 min containing 0.2% phosphoricacid, 4 mL/min, monitoring at 220 nm). MS (ESI): m/z 439.07 [M+H]⁺.Compound 824B represents a racemic mixture of antipodes. Thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 825[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-3-chloro-2-methylbenzonitrile(825)

A mixture of 4-amino-3-chloro-2-methyl-benzonitrile (23 mg, 0.14 mmol),compound 752 (44 mg, 0.21 mmol) and 4 Å molecular sieves (100 mg) in DMA(0.2 mL) was heated at 135° C. in a sealed tube for 18 h. Purificationby preparative TLC (SiO₂) eluting with 30% aetone/CHCl₃ gave compound825 (5.0 mg, 10%) as a yellow film. HPLC: 90% at 2.37 min (retentiontime) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ES): m/z 360.97 [M+H]⁺. The absolute stereochemistry ofcompound 825 is established by the known stereochemistry of theintermediate compound 752 and the retention of configuration therein.The absolute stereochemistry is as drawn in the above FIGURE andrendered by the nomenclature.

EXAMPLE 826[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzenecarbothioamide(826)

H₂S gas was condensed into a pyrex tube at −78° C. until there was 5 mLof liquid. Compound 471Di (108 mg, 0.284 mmol), Et₃N (50.0 μL, 0.341mmol) and DMF (1 mL) were added at −78° C. and the tube was sealed. Thereaction mixture was allowed to warm to rt with stirring behind a blastshield then heated at 90° C. for 50 mins at which time the color changedto green. The reaction mixture was recooled to −78° C. to check theprogress by HPLC. All the starting material was consumed, so the mixturewas allowed to warm to rt to remove H₂S, diluted with EtOAc and washedwith H₂O (4×10 mL). Purification by silica gel flash chromatographyeluting with 50% acetone/CHCl₃ gave compound 826 (116 mg, 98%) as awhite solid. HPLC: 98% at 1.90 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 415.23[M+H]⁺. The absolute stereochemistry of compound 826 is established bythe known stereochemistry of the intermediate compound 471Di and theretention of configuration therein. The absolute stereochemistry is asdrawn in the above FIGURE and rendered by the nomenclature.

EXAMPLE 827[3aR-(3aα,4β,5β,7β,7aα)]-2-[3-(trifluoromethyl)-4-(2-thiazolyl)phenyl]-5-(acetoxy)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(827i) &[3aR-(3aα,4β,5β,7β,7aα)]-2-[3-(trifluoromethyl)-4-(2-thiazolyl)phenyl]hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione(827ii)

A solution of compound 826 (61.6 mg, 0.149 mmol), bromoacetaldehydediethyl acetal (30.0 μL, 0.186 mmol) and p-toluene sulphonic acid (1 mg,cat.) in AcOH (1 mL) was heated at 100° C. for 1 h. The reaction mixturewas cooled to rt and diluted with H₂O. The mixture was extracted withEtOAc (1×10 mL) and the resulting organic layer was washed with H₂O(1×10 mL), saturated NaHCO₃ (1×10 mL) and brine (1×10 mL), then driedover MgSO₄ and concentrated in vacuo. Purification by preparative TLC(SiO₂) eluting with 30% acetone/CHCl₃ gave two products both of whichwere subjected to further purification. The less polar product waspurified further by silica gel flash chromatography eluting with 50%EtOAc/hexanes to give compound 827i (30.0 mg, 42%) as a white solid. Themore polar product was purified further by silica gel flashchromatography eluting with 10% acetone/CHCl₃ to give compound 827ii(4.6 mg, 7%) as a white solid. Compound 827i: HPLC: 99% at 3.12 min(retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 481.04 [M+H]⁺. Compound 827ii: HPLC:99% at 2.62 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm). MS (ES): m/z 439.02 [M+H]⁺. Theabsolute stereochemistry of compounds 827i & 827ii is established by theknown stereochemistry of the intermediate compound 471Di and theretention of configuration there in. The absolute stereochemistry is asdrawn in the above FIGURE and rendered by the nomenclature.

EXAMPLE 828[3aR-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3,4-dimethyl-2-pyridinecarbonitrile(828)

A mixture of 5-amino-3,4-dimethylpyridine-2-carbonitrile (30 mg, 0.20mmol), compound 752 (65 mg, 0.31 mmol) and 4 Å molecular sieves (200 mg)in DMA (1 mL) was heated at 160° C. in a sealed tube for 18 h. Thereaction mixture was filtered, the residue was washed with EtOAc and thecombined filtrates were concentrated under reduced pressure.Purification by preparative TLC (SiO₂) eluting with 90% EtOAc/hexanesgave compound 828 (42 mg, 40%) as a light pink solid. HPLC: 94% at 1.92& 2.00 min (retention time-atropisomers) (YMC S5 ODS column 4.6×50 mmeluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 342.21[M+H]⁺. The absolute stereochemistry of compound 828 is established bythe known stereochemistry of the intermediate compound 752 and theretention of configuration therein. The absolute stereochemistry is asdrawn in the above FIGURE and rendered by the nomenclature.

EXAMPLE 829[3aS-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3,4-dimethyl-2-pyridinecarbonitrile(829)

A mixture of 5-amino-3,4-dimethylpyridine-2-carbonitrile (30 mg, 0.20mmol), compound 751 (65 mg, 0.31 mmol) and 4 Å molecular sieves (200 mg)in DMA (0.25 mL) was heated at 160° C. in a sealed tube for 18 h. Thereaction mixture was filtered, the residue was washed with EtOAc and thecombined filtrates were washed with H₂O (2×10 mL), brine (1×10 mL),dried (Na₂SO₄) and concentrated under reduced pressure. Purification bysilica gel flash chromatography on silica gel eluting with 90%EtOAc/hexanes followed by preparative TLC (SiO₂) eluting with 90%EtOAc/hexanes gave compound 829 (35 mg, 33%) as a light pink solid.HPLC: 98% at 1.92 & 2.00 min (retention time-atropisomers) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 342.21 [M+H]⁺. The absolute stereochemistry of compound 829 isestablished by the known stereochemistry of the intermediate compound751 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 830

A solution of compound 791B (41 mg; 0.1 mmol), 2.0M methylamine in THF(0.2 mL; 0.4 mmol), 1-hydroxy-7-azabenzotriazole (17 mg; 0.12 mmol),EDCI (40 mg; 0.2 mmol) and diisopropylethylamine (0.075 mL; 0.4 mmol) in0.5 mL of DMF was heated to 55° C. for 3 hs. After partitioning thereaction mixture between EtOAc (20 mL) and water (20 mL), the organiclayer was washed with 1N NaOH (2×20 mL), saturated potassium bisulfatesolution (2×20 mL) and brine (20 mL). Drying (MgSO₄) and concentrationin vacuo gave an residue that was crystallized from ethyl ether toafford compound 830 (30 mg, 71%) as a white solid. HPLC: 97.5% at 1.48min (retention time) (Phenominex S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 422.30 [M+H]⁺. Compound 830represents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 831 Name 831

One drop of DMF was added to a solution of compound 792B (60 mg; 0.15mmol) and oxalyl chloride (0.026 mL; 0.3 mmol) in methylene chloride (1mL) at rt. After stirring 2 h at rt, the volatiles were removed invacuo. The residue was dissolved in ˜2 mL of isopropanol. After standing30 min at rt, the volatiles were removed in vacuo and the residue wasdissolved in EtOAc:isopropanol, 9:1 (20 mL). The solution was allowed tostand 15 min over decolorizing carbon. Filtration though celite andconcentration of the filtrate afforded compound 831 (56 mg, 83%) as alight yellow foam. HPLC: 96.9% at 1.52 min (retention time) (PhenominexS5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 2mincontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES): m/z451.08 [M+H]⁺. Compound 831 represents a racemic mixture of antipodes.The nomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 832 Name 832i & 832ii

Racemic compound 831 (0.4 g) was separated into its enantiomers bynormal phase preparative chiral HPLC (CHIRALPAK OJ 5×50 cm column;eluting with 25% MeOH/EtOH (1:1) in hexane (isocratic) at 50 mL/min) togive 170 mg of faster eluting enantiomer, compound 832i (Chiral HPLC:8.97 min; CHIRALPAK OJ 4.6×250 mm column; eluting with 20% MeOH/EtOH(1:1) in hexane at 1 mL/min); HPLC: 99% at 1.84 min (retention time)(Phenominex S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 2 mincontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES):m/z 451.06 [M+H]⁺ and 190 mg of the slower eluting enantiomer, compound832ii (Chiral HPLC: 14.79 min; CHIRALPAK OJ 4.6×250 mm column; elutingwith 20% MeOH/EtOH (1:1) in hexane at 1 mL/min); HPLC: 99% at 1.85 min(retention time) (Phenominex S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min, monitoring at254 nm); MS (ES): m/z 451.03 [M+H]⁺. The absolute stereochemistry ofcompounds 832i & 832ii has not been established. Although each compoundrepresents a single antipode, the nomenclature and structure shown doesnot reflect the absolute stereochemistry of the compound.

EXAMPLE 833

A solution of compound 792B (45 mg; 0.11 mmol), methane sulfonamide (27mg; 0.28 mmol), 4-dimethylaminopyridine (34 mg; 0.28 mmol) and EDCI (24mg; 0.12 mmol) in 1 mL of dichloromethane was stirred at rt for 18 hs.After partitioning the reaction mixture between EtOAc (25 mL) and water(25 mL), the organic layer was washed with saturated potassium bisulfatesolution (25 mL), water (25 mL) and brine (25 mL). Drying (MgSO₄) andconcentration gave an residue that was triturated with ethyl ether toafford compound 833 (29 mg, 55%) as an off-white powder. HPLC: 98% at1.44 min (retention time) (Phenominex S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 485.94 [M+H]⁺. Compound 833represents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 8343aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carb(834)

A mixture of compound 792B (100 mg; 0.24 mmol),(methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (125mg; 0.5 mmol) and triethylamine (0.15 mL; 1 mmol) in 2.5 mL of THF wasstirred at rt for 2 hs. After partitioning the reaction mixture betweenethyl ether (30 mL) and water (30 mL), the organic layer was washed withsaturated potassium bisulfate solution (30 mL), saturated sodiumbicarbonate solution (30 mL) and brine (30 mL). Drying (MgSO₄) andconcentration in vacuo afforded compound 834 (80 mg, 97%) as a whitepowder. HPLC: 99% at 1.51 min (retention time) (Phenominex S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 2 mincontaining 0.1%TFA, 4 mL/min, monitoring at 254 nm); MS (ES): m/z 390.03 [M+H]⁺.Compound 834 represents a racemic mixture of antipodes. The nomenclatureand structure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 835

A mixture of compound 793A (121 mg; 0.29 mmol) and benzylamine (0.032mL; 0.29 mmol) in 0.6 mL of THF was stirred at rt for 18 hs. Afteradding ˜5 mL of hexane, the resulting suspension was filtered and driedto afford compound 835 (135 mg, 89%) as a white powder. HPLC: 99% at1.42 min (retention time) (Phenominex S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 528.39 [M+H]⁺. Compound 835represents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 836

A mixture of compound 793A (190 mg; 0.45 mmol) and 2.0M ammonia in THF(0.3 mL; 0.6 mmol) in 0.7 mL of THF was stirred at rt. After 1 h, anadditional amount of 2.0M ammonia in THF (0.7 mL; 1.4 mmol) was addedand the reaction mixture was stirred at rt for 18 hs. The volatiles wereremoved in vacuo and the residue was triturated from hexane to affordcompound 835 (145 mg, 74%) as an off-white powder. HPLC: 95.1% at 1.28min (retention time) (Phenominex S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 438.26 [M+H]⁺. Compound 836represents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 837

A mixture of compound 793A (42 mg; 0.1 mmol) and 2.0M dimethylamine inMeOH (0.1 mL; 0.1 mmol) in 0.5 mL of THF was stirred at rt for 18 h. Thevolatiles were removed in vacuo and the residue filtered though a 0.5×5cm plug of silica gel, eluted with 50 mL of EtOAc. After concentrationof the filtrate, the light yellow residue was dissolved in ethyl etherand 0.3 mL of 1M HCl in ethyl ether was added. The volatiles wereremoved in vacuo and the solid residue was triturated from ethyl etherto afford compound 837 (25 mg, 50%) as a cream colored powder. HPLC: 99%at 1.31 min (retention time) (Phenominex S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 466.33 [M+H]⁺. Compound 837represents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 838

A mixture of compound 793A (42 mg; 0.1 mmol) and 2.0M dimethylamine inTHF (0.1 mL; 0.1 mmol) in 0.5 mL of THF was stirred at rt for 18 h. Thevolatiles were removed in vacuo and the residue filtered though a 0.5×5cm plug of silica gel, eluted with ˜50 mL of EtOAc. After concentrationof the filtrate, the yellow residue was dissolved in ethyl ether and 0.3mL of 1M HCl in ethyl ether was added. The volatiles were removed invacuo and the solid residue was triturated from ethyl ether to affordcompound 838 (22 mg, 46%) as a yellow powder. HPLC: 99% at 1.28 min(retention time) (Phenominex S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min, monitoring at254 nm); MS (ES): m/z 452.31 [M+H]⁺; Compound 838 represents a racemicmixture of antipodes. The nomenclature and structure shown does notreflect the absolute stereochemistry of the compound.

EXAMPLE 839

A. 4-Methyl-benzo[1,2,5]thiadiazole (839A)

To a solution of 2,3-diaminotoluene (5.0 g, 40.9 mmol) in pyridine (40mL) at 0° C. was added thionyl chloride (7.0 mL, 98.2 mmol) dropwise.The reaction mixture was stirred at 0° C. for 30 mins, then water (200mL) was added. The solution was extracted with dicholomethane (2×250mL). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give compound 839A (5.57 g) as adark brown liquid.

B. 4-Methyl-5-nitro-benzo[1,2,5]thiadiazole (839B)

To a solution of 4-methyl-benzo[1,2,5]thiadiazole (5.57 g, 37.1 mmol) inconc. H₂SO₄ (14.5 mL) at 0° C. was slowly added HNO₃/H₂SO₄ (3.25 mL/4.25mL). The reaction mixture was stirred at 0° C. for 20 min and then at rtfor 30 min and then was poured into iced water (200 mL). The resultingprecipitate was isolated by filtration, rinsed with water and purifiedby silica gel flash chromatography, eluting with CHCl₃ to give compound839B (1.5 g) as a yellow solid and4-methyl-7-nitrobenzo[1,2,5]thiadiazole (2.0 g) as a yellow solid.

C. 4-Methyl-benzo[1,2,5]thiadiazol-5-ylamine (839C)

4-Methyl-5-nitro-benzo[1,2,5]thiadiazole (1.4 g, 7.18 mmol) wasdissolved in THF (10 mL), acetic acid (1 mL) and water (21 mL) and ironpowder (1.4 g, 25.0 mmol, 325 Mesh) was added. The reaction mixture washeated at 80° C. for 1.5 h, cooled to rt and filtered though celite toremove the iron powder. The solution was extracted with CHCl₃ (2×250mL). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give compound 839C (1.1 g) as alight brown solid.

D. (839D)

4-Methyl-benzo[1,2,5]thiadiazol-5-ylamine (0.10 g, 0.610 mmol), 4Amolecular sieve (0.46 g) and compound 752 (0.128 g, 0.610 mmol) weredissolved in DMA (0.60 mL) in a sealed tube. The reaction mixture washeated at 190° C. for 1 h and then was cooled to rt. The solution wasfiltered though celite to remove the sieves and then the filtrate waswashed with saturated NH₄Cl (10 mL) followed by brine (10 mL). Theorganic layer was then dried over Na₂SO₄ and concentrated in vacuo toyield a yellow oil. The resulting material was purified by preparativeTLC (SiO₂), eluting with 20% acetone in CHCl₃ to give compound 839D (70mg) as a light yellow solid. HPLC: 98% at 2.87 min (retention time) (YMCS-50DS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ESI): m/z 360.19 [M+H]. The absolute stereochemistry of compound 752 isestablished by the known stereochemistry of the intermediate compound839D and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 840

4-Methyl-benzo[1,2,5]thiadiazol-5-ylamine (0.078 g, 0.47 mmol), 4 Åmolecular sieve (0.46 g) and compound 751 (0.100 g, 0.47 mmol) weredissolved in DMA (0.50 mL) in a sealed tube. The reaction mixture washeated at 190° C. for 1 h and then was cooled to rt. The solution wasfiltered though celite to remove the sieves and then the filtrate waswashed with saturated NH₄Cl (10 mL), followed by brine (10 mL). Theorganic layer was then dried over Na₂SO₄ and concentrated in vacuo toyield a yellow oil. The resulting material was purified by preparativeTLC (SiO₂), eluting with 20% acetone in CHCl₃ to give compound 840 (20mg) as a light yellow solid. HPLC: 97% at 2.87 min (retention time) (YMCS-50DS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ESI): m/z 360.30 [M+H]. The absolute stereochemistry of compound 840 isestablished by the known stereochemistry of the intermediate compound751 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 841[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-methyl-2-(trifluoromethyl)benzonitrile(841E)

A. N-(4-Chloro-3-trifluoromethylphenyl)-2,2-dimethylpropionamide (841A)

To a solution of commercially available4-chloro-3-(trifluoromethyl)aniline (15.0 g, 76.7 mmol) in anhydrous THF(200 mL) cooled to 0-5° C. was added triethylamine (11.7 mL, 84.4 mmol)followed by pivaloyl chloride (10.4 mL, 84.4 mmol) over 30 min. The icebath was removed and the mixture stirred at rt for 1 h. The mixture wasdiluted with ether and filtered. The filtrate was washed with water (2×)and brine, dried over MgSO₄, filtered and concentrated. The residue wastriturated with hexanes and the solid was filtered and dried in vacuo toafford compound 841A (20.4 g, 95%). MS (ES): m/z=280 [M+1]⁺.

B.N-(4-Chloro-2-methyl-3-trifluoromethylphenyl)-2,2-dimethylpropionamide(841B)

To a solution ofN-(4-chloro-3-trifluoromethylphenyl)-2,2-dimethylpropionamide (2.29 g,8.19 mmol) in anhydrous THF (25 mL) cooled to 0-5° C. was added asolution of 1.6 M n-butyllithium in hexanes (12.3 mL, 19.7 mmol), addedslowly so that the reaction temperature was maintained below 5° C. Thesolution was stirred at 0-5° C. for 1.5 h. A solution of iodomethane(0.56 mL, 9.01 mmol) in petroleum ether (2 mL) was added over 20 minwhile maintaining the temperature below 5° C. The suspension was stirredat 0-5° C. for 1 h and diluted with water and ether. The aqueous layerwas extracted with ether and the combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was chromatographed (silica gel), eluting with CH₂Cl₂ to affordcompound 841B (1.60 g, 67%). MS (ES): m/z=294 [M+1]⁺.

C. N-(4-Cyano-2-methyl-3-trifluoromethylphenyl)-2,2-dimethylpropionamide(841C)

A suspension ofN-(4-chloro-2-methyl-3-trifluoromethylphenyl)-2,2-dimethylpropionamide(8.36 g, 28.5 mmol) and CuCN (4.33 g, 65.5 mmol) in anhydrousN-methylpyrrolidinone (85 mL) was refluxed for 38 h. After cooling tort, the suspension was poured into ice water with stirring. Theresulting solid was filtered, washed with water and dried to yield an85:15 mixture (7.55 g) of compound 841C and 841D. The resulting mixturewas used in the next step.

D. 4-Amino-3-methyl-2-trifluoromethylbenzonitrile (841D)

A solution of the mixed product from example 841C (7.53 g, 26.5 mmol)was dissolved in 120 mL of concentrated HCl/EtOH (1:1) and was refluxedfor 14 h. After cooling to rt, the solution was concentrated in vacuo.The resulting residue was dissolved in EtOAc, washed with saturatedaqueous NaHCO₃ (2×) and brine (1×), dried over MgSO₄, filtered andconcentrated in vacuo. The residue was chromatographed (silica gel),eluting with chloroform/methanol (98:2) to furnish compound 841D (4.62g, 87%). MS (ES): m/z=201 [M+1]⁺.

E.[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-methyl-2-(trifluoromethyl)benzonitrile(841E)

4-Amino-3-methyl-2-trifluoromethylbenzonitrile (0.051 g, 0.25 mmol), 4 Åmolecular sieve (0.20 g) and compound 752 (0.059 g, 0.28 mmol) weredissolved in DMA (0.30 mL) in a sealed tube. The reaction mixture washeated at 175° C. for 30 min and then was cooled to rt. The solution wasfiltered though celite to remove the sieves and then the filtrate waswashed with saturated NH₄Cl (10 mL), followed by brine (10 mL). Theorganic layer was then dried over Na₂SO₄ and concentrated in vacuo toyield a yellow oil. The resulting material was purified by preparativeTLC (SiO₂), eluting with 25% acetone in CHCl₃ to give compound 841E (40mg) as a light brown solid. HPLC: 97% at 3.18 min (retention time) (YMCS-50DS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ESI): m/z 393.18 [M−H]⁻. The absolute stereochemistry of compound 841Eis established by the known stereochemistry of the intermediate compound752 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 842[3aS-(3aα,4β,5β,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-chloro-2-pyridinecarbonitrile(842)

Compound 752 (500 mg, 2.36 mmol), 4 Å mol sieves (1.5 g),5-amino-3-chloro-2-cyanopyridine (357 mg, 2.34 mmol) and DMA (2 mL) werecombined in a sealed tube. The mixture was heated in a pre-heatedoil-bath at 170° C. for 25 min, cooled and the sieve was removed byfiltration, eluting with EtOAc. The organics were washed 3× with water,followed by brine. The resulting organics were dried over MgSO₄ andconcentrated in vacuo. The residue was pre-adsorbed on Celite andpurified by silica gel flash chromatography with 0 to 40% acetone inCH₂Cl₂ to give Compound 842 (480 mg, 63%) as a tan solid. HPLC: 97% at2.66 min (retention time) (YMC S5 ODS-A column 4.6×50 mm Ballistic,10-90% aqueous methanol over 4 mincontaining 0.2% H₃PO₄, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 348.30 [M+H]⁺. The absolutestereochemistry of compound 842 is established by the knownstereochemistry of the intermediate compound 752 and the retention ofconfiguration there in. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 843

A. 5-Methyl-imidazo[1,2-a]pyridin-6-ylamine (843A)

2-Methyl-3-nitro-6-amino pyridine (63 mg, 0.41 mmol) was suspended in1.3 mL EtOH containing 0.3 mL conc. HCl. 2-Bromo-1,1-dimethoxy-ethane(73 μL, 0.62 mmol) was added and the resulting mixture was refluxed for8 h, at which point additional 2-bromo-1,1-dimethoxy-ethane (0.1 mL,0.85 mmol) was added. The mixture was stirred at reflux overnight,cooled and diluted with CH₂Cl₂. The organics were washed with sat.NaHCO₃ solution, dried over MgSO₄ and concentrated in vacuo. The residuewas dissolved in 4 mL AcOH/EtOAc (1:1) and the resulting solution washeated to 75° C. Iron powder (46 mg, 0.82 mmol, 325 Mesh) was added andthe mixture was stirred for 20 min. Additional iron powder (46 mg, 0.82mmol, 325 Mesh) was added and stirring was continued for 30 min. Themixture was cooled to room temperature and concentrated. The resultingresidue was purified by silica gel silica gel flash chromatography with20% MeOH in CH₂Cl₂ to give compound 843A (51 mg, 85%) as a yellow-brownsolid. HPLC: 72% at 0.18 min and 28% at 0.27 min (retention time) (YMCS5 ODS-A column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4mincontaining 0.2% H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z147.85 [M+H]⁺.

C. (843B)

In a sealed tube was placed 5-methyl-imidazo[1,2-a]pyridin-6-ylamine (46mg, 0.31 mmol), compound 20A (92 mg, 0.47 mmol), 250 mg 4 Å mol sievesand 0.3 mL DMA. The tube was sealed and heated in a pre-heated oil-bathto 170° C. for 30 min. The mixture was cooled and filtered eluting withEtOAc. The filtrate was washed 3× with water followed by brine. Theorganic layer was dried over MgSO₄, concentrated in vacuo and purifiedby preparative TLC (SiO₂) with 50% acetone in CHCl₃ to give Compound843B (32 mg, 32%) as a pale yellow solid. HPLC: 99% at 1.47 min(retention time) (YMC S5 ODS-A column 4.6×50 mm Ballistic, 10-90%aqueous methanol over 4 mincontaining 0.2% H₃PO₄, 4 mL/min, monitoringat 220 nm). MS (ES): m/z 326.39 [M+H]⁺.

EXAMPLE 844

In a sealed tube were combined 5-methyl-imidazo[1,2-a]pyridin-6-ylamine(50 mg, 0.34 mmol), compound 752 (108 mg, 0.51 mmol), MgSO₄ (102 mg,0.85 mmol), Et₃N (0.24 mL, 1.7 mmol) and 0.3 mL 1,2-dimethoxy-ethane.The tube was sealed and heated to 135° C. for 14 h. The mixture wascooled to rt, filtered to remove the sieve, eluting with MeOH, andconcentrated in vacuo. Purification of the resulting residue by silicagel flash chromatography with 0 to 10% MeOH in CH₂Cl₂ afforded compound844 (86 mg, 74%) as a tan solid. HPLC: 100% at 0.85 min (retention time)(YMC S5 ODS-A column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4mincontaining 0.2% H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z342.20 [M+H]⁺. The absolute stereochemistry of compound 844 isestablished by the known stereochemistry of the intermediate compound752 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 845

According to the procedure of Example 843,5-methyl-imidazo[1,2-a]pyridin-6-ylamine (50 mg, 0.34 mmol), compound751 (108 mg, 0.51 mmol), MgSO₄ (102 mg, 0.85 mmol), Et₃N (0.24 mL, 1.7mmol) were reacted in 0.3 mL 1,2-dimethoxyethane. Purification gavecompound 845 (79 mg, 68%) as a tan solid. HPLC: 100% at 0.85 min(retention time) (YMC S5 ODS-A column 4.6×50 mm Ballistic, 10-90%aqueous methanol over 4 mincontaining 0.2% H₃PO₄, 4 mL/min, monitoringat 220 nm). MS (ES): m/z 342.20 [M+H]⁺. The absolute stereochemistry ofcompound 845 is established by the known stereochemistry of theintermediate compound 751 and the retention of configuration therein.The absolute stereochemistry is as drawn in the above FIGURE andrendered by the nomenclature.

EXAMPLE 846

A. Imidazo[1,2-a]pyridin-6-ylamine (846A)

2-Amino-5-nitro pyridine was suspended in a 40 mL solution of EtOH/conc.HCl (3:1). To this suspension was added 2-bromo-1,1-dimethoxy-ethane(6.37 mL, 53.91 mmol) and the resulting mixture was heated to reflux for8 h, after which additional 2-bromo-1,1-dimethoxy-ethane (6.37 mL, 53.91mmol) was added. The mixture was heated at reflux overnight, cooled tort and placed in a refrigerator for 24 h. The precipitates werecollected, washed with ice-cold EtOH, air-dried and converted to thefree-based using standard procedures to afford a yellow solid. Theresulting crude yellow solid, (404 mg) was dissolved in 150 mL THF/MeOH(1:1) and the resulting solution was hydrogenated for 4 h over Pd/C (250mg, 10%) using a hydrogen balloon. The mixture was filtered thoughCelite eluting with THF/MeOH (1:1) and the filtrate was concentrated.Purification was achieved using silica gel flash chromatography with 20%MeOH in CH₂Cl₂ to give Compound 846A (241 mg, 75%) as a colorless oilwhich turns dark upon standing.

B. (846B)

In a sealed tube were combined imidazo[1,2-a]pyridin-6-yl amine (64 mg,0.48 mmol), compound 752 (148 mg, 0.71 mmol), MgSO₄ (146 mg, 1.21 mmol),Et₃N (0.34 mL, 2.40 mmol) and 0.4 mL 1,2-dimethoxy-ethane. The tube wassealed and heated to 135° C. for 14 h. The mixture was cooled, filteredthough Celite eluting with MeOH and concentrated. Purification wasachieved by silica gel flash chromatography with 10% MeOH in CH₂Cl₂ togive compound 846B (107 mg, 64%) as a pale yellow solid. HPLC: 40% at0.19 min and 60% at 0.38 min (retention time) (YMC S5 ODS-A column4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 minutes containing0.2% H₃PO₄, 4 mL/min, monitoring at 220 mm). MS (ES): m/z 328.16 [M+H]⁺.The absolute stereochemistry of compound 846B is established by theknown stereochemistry of the intermediate compound 752 and the retentionof configuration therein. The absolute stereochemistry is as drawn inthe above FIGURE and rendered by the nomenclature.

EXAMPLE 847

According to the procedure given in Example 846,imidazo[1,2-a]pyridin-6-ylamine (50 mg, 0.38 mmol), compound 751 (119mg, 0.56 mmol), MgSO₄ (114 mg, 0.95 mmol), Et₃N (0.26 mL, 1.9 mmol) werereacted in 0.35 mL 1,2-dimethoxyethane. Purification gave compound 847(87 mg, 70%) as a white solid. HPLC: 32% at 0.20 min and 68% at 0.37 min(retention time) (YMC S5 ODS-A column 4.6×50 mm Ballistic, 10-90%aqueous methanol over 4 mincontaining 0.2% H₃PO₄, 4 mL/min, monitoringat 220 nm). MS (ES): m/z 328.12 [M+H]⁺. The absolute stereochemistry ofcompound 847 is established by the known stereochemistry of theintermediate compound 751 and the retention of configuration therein.The absolute stereochemistry is as drawn in the above FIGURE andrendered by the nomenclature.

EXAMPLE 848

A. 4-Amino-2-methoxy-benzonitrile (848A)

2-Methoxy-4-nitro-benzonitrile (500 mg, 2.81 mmol) was suspended into 4mL AcOH/EtOAc (1:1) and the resulting mixture was heated to 75° C. togive a clear solution. Fe powder (313 mg, 5.61 mmol, 325 Mesh) was addedand the mixture was stirred for 30 min, after which additional Fe powder(313 mg, 5.61 mmol, 325 Mesh) was introduced. The mixture was stirred at75° C. for an additional 30 min, and then cooled to rt and filtered,eluting with EtOAc. The filtrate was concentrated in vacuo, re-dissolvedin EtOAc, filtered (eluting with EtOAc) and concentrated. Purificationwas achieved by silica gel flash chromatography with 0 to 10% MeOH inCH₂Cl₂ to give compound 848A as a tan solid.

B. (848B)

In a sealed tube were combined 4-amino-2-methoxy-benzonitrile (40 mg,0.27 mmol), compound 752 (86 mg, 0.41 mmol), MgSO₄ (81 mg, 0.68 mmol),Et₃N (0.19 mL, 1.4 mmol) and 0.25 mL 1,2-dimethoxy-ethane. The tube wasclosed and heated to 135° C. for 14 h. The mixture was cooled to rt,filtered (eluting with MeOH) and concentrated in vacuo. Purification ofthe resulting residue by silica gel flash chromatography using 0 to 100%EtOAc in CH₂Cl₂ to afforded compound 848B (36 mg, 39%) as an off-whitesolid. HPLC: 100% at 2.36 min (retention time) (YMC S5 ODS-A column4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 mincontaining 0.2%H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 341.23 [M−H]⁻. Theabsolute stereochemistry of compound 848B is established by the knownstereochemistry of the intermediate compound 752 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 849

A. 6-Amino-2-methyl-nicotinonitrile (849A)

A mixture of 6-amino-2-methyl-nicotinonitrile (500 mg, 2.67 mmol), CuCN(478 mg, 5.34 mmol) and DMA (2 mL) was stirred under nitrogen for 20 hat 170° C. The reaction mixture was cooled and added to 50 mL of a 20%aqueous solution of ethane-1,2-diamine. The layers were separated andthe aqueous layer was extracted 3× with EtOAc. The combined organicswere washed with water followed by brine, dried over MgSO₄ andconcentrated in vacuo. Purification by silica gel flash chromatographywith 0 to 100% EtOAc in CH₂Cl₂ gave compound 849A (199 mg, 56%) as awhite solid.

B. (849B)

In a sealed tube was placed 6-amino-2-methyl-nicotinonitrile (50 mg,0.38 mmol), compound 752 (119 mg, 0.56 mmol), MgSO₄ (114 mg, 0.95 mmol),Et₃N (0.26 mL, 1.9 mmol) and 0.3 mL 1,2-dimethoxy-ethane. The tube wassealed and heated to 135° C. for 14 h. The mixture was cooled to rt,filtered (eluting with MeOH) and concentrated in vacuo. The filtrate wasconcentrated and purified by silica gel flash chromatography with 0 to100% EtOAc in CH₂Cl₂ to give compound 849B (36 mg, 29%) as a whitesolid. HPLC: 100% at 1.99 min (retention time) (YMC S5 ODSA column4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 mincontaining 0.2%H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 328.04 [M+H]⁺. Theabsolute stereochemistry of compound 849B is established by the knownstereochemistry of the intermediate compound 752 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 850

A. 6-Amino-4,5-dimethyl-nicotinonitrile (850A)

A mixture of 5-bromo-3,4-dimethyl-pyridin-2-ylamine (500 mg, 2.49 mmol),CuCN (445 mg, 4.97 mmol) and DMA (3.5 mL) was stirred under nitrogen for20 h at 170° C. The reaction mixture was cooled and added to 50 mL of a20% aqueous solution of ethane-1,2-diamine. The layers were separatedand the aqueous layer was extracted 3× with EtOAc. The combined organicswere washed with water, followed by brine and dried over MgSO₄.Concentration in vacuo afforded compound 850A (362 mg, 99%) as a whitesolid.

B. (850B)

In a sealed tube were combined 6-amino-4,5-dimethyl-nicotinonitrile (50mg, 0.34 mmol), compound 752 (108 mg, 0.50 mmol), MgSO₄ (102 mg, 0.85mmol), Et₃N (0.24 mL, 1.7 mmol) and 0.3 mL 1,2-dimethoxy-ethane. Thetube was closed and heated to 135° C. for 14 h. The mixture was cooledto rt, filtered (eluting with MeOH) and concentrated in vacuo.Purification of the resulting residue by silica gel flash chromatographywith 0 to 100% EtOAc in CH₂Cl₂ afforded compound 850B (68 mg, 59%) as anoff-white solid. HPLC: 10% at 2.15 min and 82% at 2.31 min (retentiontime) (YMC S5 ODS-A column 4.6×50 mm Ballistic, 10-90% aqueous methanolover 4 mincontaining 0.2% H₃PO₄, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 342.06 [M+H]⁺. The absolute stereochemistry of compound 850Bis established by the known stereochemistry of the intermediate compound752 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 851

A. 6-Amino-4-methyl-nicotinonitrile (851A)

A mixture of 5-bromo-4-methyl-pyridin-2-ylamine (500 mg, 2.67 mmol),CuCN (478 mg, 5.34 mmol) and DMA (2 mL) was stirred under nitrogen for20 h at 170° C. The reaction mixture was cooled and added to 50 mL of a20% aqueous solution of ethane-1,2-diamine. The layers were separatedand the aqueous layer was extracted 3× with EtOAc. The combined organicswere washed with water followed by brine and dried over MgSO₄.Concentration in vacuo afforded compound 851A (309 mg, 87%) as a whitesolid.

B. (851B)

In a sealed tube was placed 6-amino-4-methyl-nicotinonitrile (50 mg,0.38 mmol), compound 752 (119 mg, 0.56 mmol), MgSO₄ (114 mg, 0.95 mmol),Et₃N (0.26 mL, 1.9 mmol) and 0.3 mL 1,2-dimethoxy-ethane. The tube wassealed and heated to 135° C. for 14 h. The mixture was allowed to coolto rt and filtered, eluting with MeOH. The filtrate was concentrated invacuo and purified by silica gel flash chromatography with 0 to 100%EtOAc in CH₂Cl₂ to give compound 851B (67 mg, 54%) as a white solid.HPLC: 100% at 1.95 min (retention time) (YMC S5 ODS-A column 4.6×50 mmBallistic, 10-90% aqueous methanol over 4 mincontaining 0.2% H₃PO₄, 4mL/min, monitoring at 220 nm). MS (ES): m/z 328.04 [M+H]⁺. The absolutestereochemistry of compound 851B is established by the knownstereochemistry of the intermediate compound 752 and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 852

A. tert-Butyl-(2,5-dimethyl-furan-3-ylmethoxy)-dimethyl-silane (852A)

In a dry 100 mL round-bottom flask was prepared a solution of methyl2,5-dimethyl-3-furoate (2.00 g, 13.0 mmol) in anhydrous Et₂O (10 mL)under an inert atmosphere. To this solution was added dropwise a 1.0 Msolution of LiAlH₄ in Et₂O (13 mL, 13 mmol) at 0° C. The resultingsuspension was stirred at 0° C. for 30 min and was then allowed to warmto rt, where it was kept for 4 h. The reaction was quenched by thecareful addition of solid Na₂SO₄.10H₂O (excess) and Celite (excess). Tofacilitate stirring, Et₂O was added as necessary. The resulting mixturewas stirred overnight, filtered and carefully concentrated in vacuo toyield the volatile alcohol which was dissolved in anhydrous DMF (5 mL)under an inert atmosphere. To this solution was added imidazole (1.32 g,19.5 mmol) and TBSCl (2.05 g, 13.6 mmol) and the mixture was stirred for6 h. The reaction mixture was diluted with EtOAc and water was added.The layers were separated and the organic layer was washed several timeswith water. The organics were dried over MgSO₄, concentrated in vacuoand purified by silica gel flash chromatography with 0 to 50% EtOAc inhexanes yielding compound 852A (3.08 g, 99%) as a colorless oil.

B. (852B)

In a sealed-tube were combinedtert-butyl-(2,5-dimethyl-furan-3-ylmethoxy)dimethyl-silane (2.60 g, 10.8mmol),4-(2,5-dihydro-2,5-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(1.44 g, 5.41 g) and THF (1 mL). The tube was sealed and quickly heatedto 95° C. to yield an almost clear solution. The mixture was thenallowed to cool to rt and was stirred at rt overnight. Purification wasachieved by silica gel flash chromatography with 0 to 100% EtOAc inhexanes to give compound 852B (2.37 g, 86%) as a white solid.

C. (852C)

A solution Compound 852B of (1.4 g, 2.8 mmol) in EtOAc (50 mL) washydrogenated over Pd/C (10%, 800 mg) for 6 h using a hydrogen balloon.The mixture was filtered, eluting with EtOAc, and concentrated in vacuo.Purification was achieved using silica gel flash chromatography with 0to 100% EtOAc in hexanes to afford Compound 852C (0.9 g, 64%) as a whitefoam.

D

Compound 852C (0.9 g, 1.8 mmol) was dissolved in 7 mL EtOH containing 2%conc. HCl at rt and the resulting mixture was stirred for 2 h. Thereaction mixture was carefully poured into sat. NaHCO₃ solution and theaqueous layer was extracted twice with EtOAc. The combined organics weredried over MgSO₄, concentrated in vacuo and purified by silica gel flashchromatography with 0 to 100% EtOAc in CH₂Cl₂ to afford a racemicmixture of compound 852Di & 852Dii (0.7 g, 100%) as a white solid. Theracemic material was separated into its enantiomers by normal phasepreparative chiral HPLC (CHIRALPAK OJ 5×50 cm column; eluting with 30%MeOH/EtOH (1:1) in heptane (isocratic) at 50 mL/min) to give the fastereluting enantiomer compound 852Di (Chiral HPLC: 5.56 min; CHIRALPAK OJ4.6×250 mm column; eluting with 30% MeOH/EtOH (1:1) in heptanecontaining 0.1% DEA at 1 mL/min) and the slower eluting anantiomercompound 852Dii (Chiral HPLC: 7.01 min; CHIRALPAK OJ 4.6×250 mm column;eluting with 30% MeOH/EtOH (1:1) in heptane containing at 1 mL/min). Theabsolute stereochemistry of compounds 852Di & 852Dii has not beenestablished. Although each compound represents a single antipode, thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 853(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(853)

Triphenylphosphine (0.066 g, 0.254 mmol) anddi-tert-butyl-azodicarboxylate (0.058 g, 0.254 mmol) in THF (0.5 mL)were stirred at rt under N₂ for 10 min, then6-trifluoromethyl-4-pyrimidinol (0.042 g, 0.254 mmol) was added. Thereaction mixture was stirred under N₂ for another 15 min, followed bythe addition of a racemic mixture of compounds 852Di & 852Dii (0.050 g,0.127 mmol). The reaction was allowed to proceed for 2 h, at which pointCH₂Cl₂ (15 mL) was added. The organic layer was isolated and then washedconsecutively with 1N NaOH (15 mL), brine (15 mL) and dried over MgSO₄and concentrated in vacuo. The resulting solid was purified by silicagel chromatograph, eluting with EtOAc in Hexane from 0% to 100%, to givecompound 853 (60 mg) as a white solid. HPLC: 99% at 4.083 min (retentiontime) (YMC S-50DS-A column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoringat 220 nm). MS (ESI): m/z 541.06 [M+H]. Compound 853 represents aracemic mixture of antipodes. The nomenclature and structure shown doesnot reflect the absolute stereochemistry of the compound.

EXAMPLE 854

In a sealed tube was prepared a mixture of compound 852Di (150 mg, 0.38mmol), MeI (0.24 mL, 3.8 mmol) and Ag₂O (881 mg, 3.8 mmol) in 2 mLCH₃CN. The tube was sealed and heated to 80° C. overnight. The mixturewas cooled to rt, filtered, eluting with EtOAc, and concentrated.Purification was achieved by silica gel flash chromatography with 0 to100% EtOAc in hexanes to give compound 854 (49 mg, 32%) as a colorlessoil. HPLC: 97% at 3.58 min (retention time) (YMC S5 ODS-A column 4.6×50mm Ballistic, 10-90% aqueous methanol over 4 mincontaining 0.2% H₃PO₄, 4mL/min, monitoring at 220 nm). MS (ES): m/z 407.20 [M+H]⁺. The absolutestereochemistry of compound 854 has not been established. Although thecompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 855

Compound 852Dii (150 mg, 0.38 mmol), MeI (0.24 mL, 3.8 mmol) and Ag₂O(881 mg, 3.8 mmol) were reacted in 2 mL CH₃CN and the reaction mixturepurified as described for Example 854 to afford compound 855 (45 mg,29%) as a colorless oil. HPLC: 98% at 3.58 min (retention time) (YMC S5ODS-A column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4mincontaining 0.2% H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z407.19 [M−H]⁻. The absolute stereochemistry of compound 855 has not beenestablished. Although the compound represents a single antipode, thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 856

To a solution of compound 852B (835 mg, 1.65 mmol) in 10 mL THF wasadded a 1.0M solution of BH₃.THF (3.3 mL, 3.30 mmol) dropwise at 0° C.The resulting mixture was stirred at 0° C. for 2 h, after which 15 mLEtOH, 5 mL THF, 30 mL pH 7 phosphate buffer and 2.1 mL 30% H₂O₂ wereadded. The resulting mixture was stirred for 2 h at 0° C. after whichwater and EtOAc were added. The layers were separated and the aqueouslayer was extracted again with EtOAc. The combined organic phases werewashed with 10% Na₂S₂O₃-solution followed by brine. The organics weredried over MgSO₄, concentrated and purified by flash chromatography with0 to 25% EtOAc in CH₂Cl₂. The material was dissolved in 8 mL EtOHcontaining 2% conc. HCl and the resulting mixture was stirred for 2 h.The reaction mixture was diluted with EtOAc and carefully poured intosat. NaHCO₃-solution. The layers were separated and the aqueous layerwas extracted again with EtOAc. The combined organic layers were driedover MgSO₄ and concentrated in vacuo. The resulting racemic material wasseparated into its enantiomers by normal phase preparative chiral HPLC(CHIRALPAK OD 5×50 cm column; eluting with 15% MeOH/EtOH (1:1) inheptane (isocratic) at 50 mL/min) to give the faster eluting compound856i (128 mg) (Chiral HPLC: 13.64 min; CHIRALPAK OD 4.6×250 mm column;eluting with 15% MeOH/EtOH (1:1) in heptane containing at 1 mL/min) andthe slower eluting compound 856ii (137 mg, 39% combined yield) (ChiralHPLC: 16.31 min; CHIRALPAK OD 4.6×250 mm column; eluting with 15%MeOH/EtOH (1:1) in heptane at 1 mL/min).). MS (ES): m/z 411.01 [M+H]⁺.The absolute stereochemistry of compounds 856i & 856ii has not beenestablished. Although each compound represents a single antipode, thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 857

A. (857A)

Compound 798i was converted to compound 857A by the procedure describedin Example 774. HPLC: 95% at 4.307 min (retention time) (YMC S5 ODS-Acolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

B. (857B)

Compound 857A was converted to compound 857B by the procedure describedin Example 774. HPLC: 100% at 2.89 min (retention time) (YMC S5 ODSAcolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 381.16 [M+H]⁺.

C. (857C)

Compound 857B (0.100 g, 0.26 mmol), MeI (0.163 mL, 2.6 mmol), Ag₂O(0.603 g, 2.60 mmol) and acetonitrile (2.5 mL) were added to a highpressure reaction vessel. The vessel was sealed and heated to 75° C.After 16 h, the reaction was cooled to rt, diluted with EtOAc andfiltered through celite, rinsing with EtOAc. The crude material waspurified by flash chromatography on silica eluting with 0-5-8% acetonein chloroform to give compound 857C as a white solid. HPLC: 90% at 2.887min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 395.07 [M+H]⁺. The absolutestereochemistry of compound 857C has not been established. Although thecompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 858

A. (858Ai & 858Aii)

Compound 857B (2.50 g, 6.57 mmol) was dissolved in THF (10.0 mL) at 22°C. and 1 N NaOH (10.0 mL) was added. After 1 h, THF (10.0 mL), 1 N HCl(1.10 mL) and brine (10.0 mL) were added. The mixture was then extractedonce with EtOAc (20.0 mL) and twice with 1:1 THF/EtOAc (20.0 mL). Thecombined organics were dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give compounds 858Ai and 858Aii (1:1 by HPLC)as a white solid. No was purification necessary. HPLC: 100% at 2.383 and2.573 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

B. (858B)

Compounds 858Ai and 858Aii were suspended in a mixture of THF (50.0 mL)and AcOH (20.0 mL) and heated to 60° C. for 16 h. The reaction becamehomogenous after 4 h. The reaction was cooled to 22° C. and concentratedin vacuo. Toluene (20.0 mL) was then added and mixture heated to 90° C.for 4 h until all product was dissolved. The mixture was then cooled to22° C. and left standing for 20 h. Compound 858B precipitates fromsolution over the 20 h period. The product was filtered and rinsed withtoluene followed by drying in vacuo. Compound 858B (1.10 g) was isolatedas an off-white solid and used without further purification. ¹H NMR(DMSO-d⁶): δ=4.91 (d, 1H, J=6.2 Hz), 3.97 (dd, 1H, J=3.9, 6.2 Hz), 3.82(d, 1H, J=7.6 Hz), 3.31 (d, 1H, J=7.6 Hz), 2.27 (dd, 1H, J=10.2, 12.8Hz), 1.77 (s, 3H), 1.49 (m, 1H) and 1.47 ppm (s, 3H). The absolutestereochemistry of compound 858B has not been established. Although thecompound represents a single antipode, the nomenclature and structureshown does not reflect the absolute stereochemistry of the compound.

EXAMPLE 859(3aα,4β,5α,6β,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-6-cyano-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, methyl ester (859)

A mixture of compound 792A (84 mg; 0.2 mmol), KCN (15 mg; 0.22 mmol) andammonium chloride (12 mg; 0.22 mmol) in 1 ml of DMF and 0.25 ml of waterwas stirred at rt for 18 hr. A precipitant formed on standing overnight.After adding an additional 10 ml of water, the suspension was filteredand the filter cake was washed with water. Drying and trituration withhexane afforded compound 859 (25 mg, 28%) as a tan powder. HPLC: 95% at1.67 min (retention time) (Phenominex S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 448.29 [M+H]⁺. Compound 859represents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 860

A mixture of compound 792A (44 mg; 0.1 mmol) and acetic anhydride (0.25ml) was heated to 60° C. for 2 hr. The volatiles were removed in vacuoand the residue was co-evaporated from heptane (3×2 ml) to affordcompound 860 (47 mg, 99%) as a white powder. HPLC: 95.8% at 1.49 min(retention time) (Phenominex S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min, monitoring at254 nm); MS (ES): m/z 480.35 [M+H]⁺. Compound 860 represents a racemicmixture of antipodes. The nomenclature and structure shown does notreflect the absolute stereochemistry of the compound.

EXAMPLE 861

Sodium hydride, 60% in mineral oil (120 mg; 3 mmol) was added inportions over 10 min to a solution of compound 792A (1.9 g; 4.5 mmol)and acetone oxime (667 mg; 9 mmol) in THF at rt. After stirring 45 min,the reaction mixture was partitioned between brine (100 ml) and EtOAc(150 ml). The organic layer was washed with brine (50 ml), dried (MgSO₄)and concentrated in vacuo. The residue was chromatographed on a 5×20 cmsilica gel column, eluting with 1000 ml of 25% EtOAc/hexane and 500 mlof 40% EtOAc/hexane. Concentration of the pure fractions in vacuoafforded compound 861 (1.75 g, 80%) as a white powder. HPLC: 98% at 1.82min (retention time) (Phenominex S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 494.05 [M+H]⁺. Compound 861represents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 862(3aα,4β,5α,6β,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, methyl ester (862)

A mixture of compound 861 (1.75 g; 3.5 mmol) and zinc dust (6.07 g,87.50 mA) in 19 ml of formic acid was refluxed for 20 min. After coolingto rt, the reaction mixture was diluted with ˜50 ml of EtOAc andfiltered though celite. The filtrate was diluted with ˜200 ml of EtOAcand the organic layer was washed with water (200 ml), 0.5M NaOH (2×200ml), water (200 ml) and brine (100 ml). Drying over MgSO₄ andconcentration in vacuo gave a residue that was chromatographed on a2.5×20 cm silica gel column, eluting with 1000 ml of 40% EtOAc/hexaneand 500 ml of 50% EtOAc/hexane. Concentration of the pure fractions invacuo afforded compound 862 (820 g, 54%) as a colorless foam. HPLC: 99%at 1.47 min (retention time) (Phenominex S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 438.99 [M+H]⁺. Compound 862represents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 863[3aS-(3aα,4β,5α,6β,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, methyl ester (863i) &[3aS-(3aα,4β,5α,6β,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, methyl ester (863ii)

Racemic compound 862 (0.8 g) was separated into its enantiomers bynormal phase preparative chiral HPLC (CHIRALPAK OD 5×50 cm column;eluting with 15% EtOH in hexanes (isocratic) at 50 mL/min) to give 355mg of faster eluting compound 863i (Chiral HPLC: 8.89 min; CHIRALPAK OD4.6×250 mm column; eluting with 15% EtOH in hexanes at 2 mL/min); HPLC:99% at 2.91 min (retention time) (YMC S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 2 mincontaining 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm); MS (ES): m/z 471.00 [M+MeOH]⁺ and 330mg of the slower eluting compound 863ii (Chiral HPLC: 12.30 min;CHIRALPAK OD 4.6×250 mm column; eluting with 15% EtOH in hexanes at 2mL/min); HPLC: 99% at 2.89 min (retention time) (YMC S5 ODS column4.6×50 mm eluting with 10-90% aqueous methanol over 2 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm); MS (ES): m/z 471.99[M+MeOH]⁺. The absolute stereochemistry of compounds 863i & 863ii hasnot been established. Although each compound represents a singleantipode, the nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 864(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, methyl ester (864)

A mixture of compound 792A (210 mg; 0.5 mmol), phenylsilane (0.13 ml, 1mmol) and Mn(acac)₂ (5 mg; 0.01 mmol) in 2.5 ml isopropanol and 0.25 mlof THF was stirred 3 days at rt in open air. After adding 5% sodiumbisulfite solution (5 ml) and stirring 30 min, the reaction mixture waspartitioned between EtOAc (30 ml) and water (30 ml). Washing the organiclayer with brine (20 ml), followed by drying over MgSO₄ andconcentration in vacuo, afforded a residue that was chromatographed on a2.5×15 cm silica gel column, eluting with 50% EtOAc/hexane.Concentration of the pure fractions in vacuo, afforded compound 864 (109mg, 50%) as a white powder. HPLC: 98.6% at 1.18 min (retention time)(Phenominex S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanolover 2 mincontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES):m/z 438.98 [M+H]⁺. Compound 864 represents a racemic mixture ofantipodes. The nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 865(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacids (1-methylethyl) ester (865C)

A. 2,5-Dimethyl-furan-3-carboxylic acid isopropyl ester (865A)

Isopropanol (5 ml) was added to a solution of2,5-dimethylfuran-3-carbonylchloride (1.64 g; 10.3 mmol) in 15 ml ofmethylene chloride at rt. After allowing the reaction mixture to standat rt for 30 mins, the volatiles were removed in vacuo and the residuewas co-evaporated from isopropanol to afford compound 865A (1.8 g, 96%)as a light amber liquid. ¹HNMR (CDCl₃): δ 1.30 (d, j=6.5 Hz, 6H), 2.23(s, 3H), 2.52 (s, 3H), 5.14 (m, 1H), 6.21 (s, 1H).

B.(3aα,4β,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)tetrahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, (1-methylethyl)ester (865B)

A mixture of4-(2,5-dihydro-2,5-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(851 mg; 3.2 mmol) and compound 865A (1.7 g; 9.4 mmol) was heated to140° C. for 4 h. After allowing the mixture to cool to rt and stand 4days, the reaction mixture was chromatographed on a 5×25 cm silica gelcolumn, eluting with 25% EtOAc/hexane. Concentration of the purefractions in vacuo afforded compound 865B (869 mg, 60%) as thick yellowoil. Due to the instability of this compound, it was stored at −20C andused promptly.

C.(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, (1-methylethyl)ester (865C)

Compound 865B (224; 0.5 mmol) was converted to compound 865C using theprocedure described in Example 791B to afford compound 865C (82 mg, 35%)as a white powder. HPLC: 98.4% at 1.18 min (retention time) (PhenominexS5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 2mincontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES): m/z466.98 [M+H]⁺. Compound 865C represents a racemic mixture of antipodes.The nomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 866(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-N,N-dimethyl-1H-isoindole-5-carboxamide(866C)

A. 2,5-Dimethyl-furan-3-carboxylic acid dimethylamide (866A)

A solution of 2,5-dimethylfuran-3-carbonylchloride (2.19 g; 13.8 mmol)in 10 ml of THF was added to a 2M solution of dimethylamine in dioxane(21 ml; 42 mmol) in 80 ml of THF at rt. After stirring for 1 hr, thevolatiles were removed in vacuo and the residue was partitioned betweenEtOAc (100 ml) and water (100 ml). The organic layer was washed withsaturated potassium bisulfate solution (100 ml), 1N NaOH (50 ml) andbrine (50 ml). Drying over MgSO₄ and concentration in vacuo affordedcompound 866A (1.84 g, 80%) as an amber liquid. ¹HNMR (CDCl₃): δ 2.23(s, 3H), 2.33 (s, 3H), 3.04 (s, 6H), 5.96 (s, 1H).

B. (866B)

A mixture of4-(2,5-dihydro-2,5-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile(1.45 mg; 5.4 mmol) and compound 866A (1.82 g; 10.9 mmol) was heatedneat to 125° C. for 1 hr. After allowing the mixture to cool to rtovernight, the reaction mixture was dissolved in ˜75 ml of EtOAc.Treatment with decolorizing carbon, filtration through celite andconcentration in vacuo of the filtrate gave a residue that was dissolvedin ˜20 ml of ethyl ether. Addition of ˜30 ml of hexane, followed byfiltration and drying afforded compound 866B (1.89 g, 81%) as light pinksolid.

C.(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-N,N-dimethyl-1H-isoindole-5-carboxamide(866C)

Compound 866B (433; 1 mmol) was converted to compound 866C using theprocedure described in Example 792B to afford compound 866C (85 mg, 18%)as a white powder. HPLC: 97.9% at 1.39 min (retention time) (PhenominexS5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 2mincontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES): m/z452.00 [M+H]⁺. Compound 866C represents a racemic mixture of antipodes.The nomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 867

One drop of DMF was added to a solution of compound 792B (50 mg; 0.125mmol) and oxalyl chloride (0.03 ml; 0.36 mmol) in methylene chloride (1ml) at rt. After stirring 1.5 h at rt, the volatiles were removed invacuo. The residue was treated with 1 ml of 1,3-hexafluoro-2-propanol,followed by 0.04 ml of pyridine and 2 mg of 4-dimethylpyridine. Afterstirring 18 h. at rt the reaction mixture was partitioned between EtOAc(20 ml) and saturated sodium bicarbonate solution (20 ml). The organiclayer was washed with saturated potassium bisulfate solution (20 ml) andbrine (20 ml). Drying over MgSO₄ and concentration in vacuo afforded aresidue that was chromatographed on a 2.5×15 cm silica gel column,eluting with 25% EtOAc/hexane. Concentration of the pure fractions invacuo afforded compound 867 (36 mg, 52%) as a white solid. HPLC: 99% at1.96 min (retention time) (Phenominex S5 ODS column 4.6×50 mm elutingwith 10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 558.00 [M+H]⁺. Compound 867represents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 868(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, propyl ester (868B)

A(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid (868A)

1N NaOH (2.2 ml; 2.2 mmol) was added to a solution of compound 867 (238mg; 0.54 mmol) in 5 ml of methanol at rt. After stirring 5 h at rt, thevolatiles were removed in vacuo and the residue was treated with 2 ml oftrifluoroacetic acid for 18 hr. Concentration of the reaction mixture invacuo, followed by co-evaporation from toluene (3×8 ml) gave a residuethat was partitioned between EtOAc (40 ml) and brine (20 ml). Dryingover MgSO₄ and concentration in vacuo afforded a solid that wastriturated with hexane to afford compound 868A (120 mg, 53%) as a creamcolored solid. HPLC: 93% at 1.35 min (retention time) (Phenominex S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 2mincontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES): m/z425.08 [M+H]⁺.

B.(3aα,4β,5α,7β,7aα)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid, propyl ester (868B)

Oxalylchloride (0.18 ml, 2 mmol) was added to a solution of compound868A (135 mg; 0.32 mmol) in 4 ml of THF at room rt. Bubbling wasobserved immediately. One drop of DMF was added and the reaction mixturewas stirred 4 hrs. After adding 2 ml of n-propanol and stirring 18 h atrt, the reaction mixture was partitioned between EtOAc (30 ml) and water(30 ml). The organic layer was washed with saturated sodium bicarbonatesolution (30 ml), dried over MgSO₄ and concentrated in vacuo. Theresidue was chromatographed on a 2.5×15 cm silica gel column, elutingwith 25% EtOAc/hexane. The pure fractions were concentrated in vacuo toafford compound 868B (78 mg, 52%) as a white powder. HPLC: 95.4% at 1.63min (retention time) (Phenominex S5 ODS column 4.6×50 mm eluting with10-90% aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min,monitoring at 254 nm); MS (ES): m/z 467.10 [M+H]⁺. Compound 868Brepresents a racemic mixture of antipodes. The nomenclature andstructure shown does not reflect the absolute stereochemistry of thecompound.

EXAMPLE 869

30% Hydrogen peroxide (0.1 ml) was added to a solution of compound 748(36 mg; 0.1 mmol) in 1 ml of AcOH at 100 C. Four additional 0.1 mlaliquots of 30% hydrogen peroxide were added at 30 min intervals to thereaction mixture. Water (8 ml) was added to the reaction mixture 30minutes after the last addition of 30% hydrogen peroxide. After coolingto rt and standing 2 days, the resulting suspension was filtered and thefilter cake was washed with water. After drying, the solid was dissolvedin ˜2 ml of acetone and the solution was applied to a SiO₂ preparativethin layer chromatography plate. Elution with 30% acetone/chloroform,extraction of the more polar band, filtration and concentration affordedcompound 869 (6 mg, 16%) as an off-white solid. HPLC: 99% at 1.06 min(retention time) (Phenominex S5 ODS column 4.6×50 mm eluting with 10-90%aqueous methanol over 2 mincontaining 0.1% TFA, 4 mL/min, monitoring at254 nm); MS (ES): m/z 380.43 [M+H]⁺. Compound 869 represents a racemicmixture of antipodes. The nomenclature and structure shown does notreflect the absolute stereochemistry of the compound.

EXAMPLE 870

A racemic mixture of compound 852Di & 852Dii (150 mg, 0.38 mmol) wasdissolved in THF (2 mL) under nitrogen and 2-nitrophenyl selenocyanate(202 mg, 0.89 mmol) followed by PBu₃ (0.22 mL, 0.89 mmol) was added. Theresulting mixture was stirred for 20 h, concentrated and purified byflash chromatography with 0 to 100% EtOAc in hexanes. The resultingproduct was dissolved in THF (11 mL) and treated with 2 mL 30% H₂O₂ at0° C. The reaction mixture was stirred for 10 min, then warmed to rt andstirred overnight. The reaction was quenched by the addition of 5%Na₂S₂O₃-solution and brine. The layers were separated and the aqueouslayer was extracted 2× with CH₂Cl₂. The combined organic layers weredried over MgSO₄, concentrated in vacuo and purified by flashchromatography with 0 to 100% EtOAc in hexanes to give compound 870 (114mg, 80%) as a yellow solid. HPLC: 100% at 3.67 min (retention time) (YMCS5 ODS-A column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4mincontaining 0.2% H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z375.23 [M−H]⁻. Compound 870 represents a racemic mixture of antipodes.The nomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 871 871Bi & 871Bii

A. (871A)

To a solution of a racemic mixture of compounds 852Di & 852Dii (33 mg,0.09 mmol) in 0.5 mL acetone/0.4 mL water was added a 50% wt. solutionof NMO in water (22 μL, 0.11 mmol) followed by a 4% wt. solution of OsO₄in water (54 μL, 8.7 μmol). The resulting mixture was stirred for 12 hand the reaction was quenched by the addition of 5% Na₂S₂O₃-solution.CH₂Cl₂ was added, the layers were separated and the aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were dried overMgSO₄, concentrated in vacuo and purified by SiO₂ preparative TLC with40% acetone in CH₂Cl₂ to give racemic compound 871A (30 mg, 83%) as awhite solid. HPLC: 100% at 2.91 min (retention time) (YMC S5 ODSA column4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 mincontaining 0.2%H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 469.26 [M+OAc]⁻.Compound 871A represents a racemic mixture of antipodes. Thenomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

B. (871Bi & 871Bii)

Racemic compound 871A was separated into its enantiomers by normal phasepreparative chiral HPLC (CHIRALPAK OJ 5×50 cm column; eluting with 30%MeOH/EtOH (1:1) in heptane (isocratic) at 50 mL/min) to give the fastereluting antipode compound 871Bi (Chiral HPLC: 7.35 min; CHIRALPAK OJ4.6×250 mm column; eluting with 30% MeOH/EtOH (1:1) in heptane at 1mL/min) and the slower eluting antipode compound 871Bii (Chiral HPLC:11.49 min; CHIRALPAK OJ 4.6×250 mm column; eluting with 30% MeOH/EtOH(1:1) in heptane at 1 mL/min). The absolute stereochemistry of compounds871Bi & 871Bii has not been established. Although each compoundrepresents a single antipode, the nomenclature and structure shown doesnot reflect the absolute stereochemistry of the compound.

EXAMPLE 872(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[difluoromethyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(872)

A racemic mixture of compounds 852Di & 852Dii (50 mg, 0.13 mmol) wasdissolved under nitrogen in 1 mL CH₃CN and CuI (2 mg, 8.9 μmol) wasadded. This mixture was heated to 45° C. and2-(fluorosulfonyl)difluoroacetic acid (27 mg, 0.15 mmol) was added viasyringe. The reaction mixture was stirred for 1.5 h at 45° C. and thenallowed to cool to rt. The reaction was quenched by the addition ofwater and CH₂Cl₂. The layers were separated and the aqueous layer wasextracted with CH₂Cl₂. The combined organic phases were dried overMgSO₄, concentrated in vacuo and purified twice by SiO₂ flashchromatography with 0 to 100% EtOAc in hexanes to afford compound 872(10 mg, 18%) as a white foam. HPLC: 92% at 3.72 min (retention time)(YMC S5 ODS-A column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4mincontaining 0.2% H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z443.22 [M−H]⁻. Compound 872 represents a racemic mixture of antipodes.The nomenclature and structure shown does not reflect the absolutestereochemistry of the compound.

EXAMPLE 873 873i & 8731i

Compound 471Di (50 mg, 0.13 mmol), CuI (2 mg, 8.9 μmol) and2-(fluorosulfonyl)difluoroacetic acid (28 mg, 0.16 mmol) were reacted in1 mL CH₃CN and purified as described in Example 872. Compounds 873i &873ii (15 mg, 0.03 mmol) were obtained as a inseparable 6:1 mixture asdetermined by ¹H-NMR. HPLC: 91% at 3.64 min (retention time) (YMC S5ODS-A column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4mincontaining 0.2% H₃PO₄, 4 mL/min, monitoring at 220 nm). MS (ES): m/z489.22 [M+OAc]⁻. Compounds 873i & 873ii each represent a racemic mixtureof antipodes. The nomenclature and structure shown does not reflect theabsolute stereochemistry of the compound.

EXAMPLE 874 874i & 874ii

Triphenylphosphine (0.067 g, 0.254 mmol) anddi-tert-butyl-azodicarboxylate (0.059 g, 0.254 mmol) in THF (1 mL) werestirred at rt under N₂ for 10 min, then saccharin (0.047 g, 0.254 mmol)was added. The reaction mixture was stirred under N₂ for another 15 min,followed by the addition of compound 429i (0.050 g, 0.127 mmol). Thereaction was allowed to proceed for 24 h, at which point CH₂Cl₂ (15 mL)was added. The organic layer was isolated and then washed consecutivelywith 1N NaOH (15 mL), brine (15 mL) and dried over MgSO₄ andconcentrated in vacuo. The resulting solid was purified by SiO₂preparative TLC eluting with 25% acetone in CHCl₃, to give compound 874i(18 mg, 25%) as a white solid (HPLC: 91% at 2.96 min (retention time)(YMC S-50DS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanolover 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm). MS (ESI): m/z 559.42 [M+H]⁺) and compound 874ii (18 mg, 25%) as awhite solid (HPLC: 93% at 2.85 min (retention time) (YMC S-50DS-Acolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ESI): m/z 557.12 [M−H]⁻). The absolute stereochemistry of compounds874i & 874ii has not been established. Although each compound representsa single antipode, the nomenclature and structure shown does not reflectthe absolute stereochemistry of the compound.

EXAMPLE 875[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-cyclopropyloxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(875B)

A. (875A)

A solution of compound 471Di (300 mg, 0.79 mmol), mercurictrifluoroacetate (17 mg, 0.04 mmol) in tetrahydrofuran (THF, 1.5 mL) andethyl vinyl ether (3 mL) in a thick-walled sealed tube was heated to 45°C. for 48 h. The tube was cooled, opened and the reaction mixture wasconcentrated in vacuo to give an oil. The crude material was purified bysilica gel flash chromatography eluting with 1:4:4 EtOAc/methylenechloride/heptane to give compound 875A (115 mg, 36%) as a white solid.HPLC: 99% at 3.80 min (retention time) (YMC S5 ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 407.09[M+H]⁺. The absolute stereochemistry of compound 875A is established bythe known stereochemistry of the intermediate compound 471Di and theretention of configuration therein. The absolute stereochemistry is asdrawn in the above FIGURE and rendered by the nomenclature.

B.[3aR-(3aα,4β,5⊕,7β,7aα)]-4-(Octahydro-5-cyclopropyloxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile(875B)

To a solution of compound 875A (100 mg, 0.25 mmol) in dry methylenechloride (5 mL) cooled to 5° C. was added, dropwise, diethylzincsolution (1.0M in hexanes, 1.4 mL, 1.4 mmol). The reaction mixture waswarmed to rt, then diiodomethane (80 mL, 1.0 mmol) was introduced. After3 h, HPLC indicated the reaction was ⅔ complete. Two additional portionsof diethylzinc and diiodomethane were successively added then thereaction mixture cooled in an ice-bath, quenched with water, andpartitioned between 1 M HCl solution (20 mL) and EtOAc (20 mL). Theorganic phase was separated, dried over sodium sulfate, concentrated invacuo and purified by silica gel flash chromatography eluting with 2:3EtOAc/heptane to give compound 875B as a white solid. HPLC: 100% at 3.72min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 421.08 [M+H]⁺. The absolutestereochemistry of compound 875B is established by the knownstereochemistry of the intermediate compound 471Di and the retention ofconfiguration therein. The absolute stereochemistry is as drawn in theabove FIGURE and rendered by the nomenclature.

EXAMPLE 876 876

A racemic mixture of compounds 808& 809 (0.057 g, 0.15 mmol) wasdissolved in 2 mL of CH₂Cl₂. Triethylamine (0.018 g, 0.18 mmol), acatalytic amount of DMAP, and 4-fluorobenzoyl chloride (0.075 g, 0.48mmol) were added and the reaction was stirred for 6 h. The reactionmixture was diluted with CH₂Cl₂ and washed sequentially with 1N HCl, 10%K₂CO₃, and brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by preparative TLC on silica gel using 2:1EtOAc/hexanes as eluent. Removal of solvent gave compound 876 (0.066 g,70%) as a white solid. HPLC: 100% at 3.94 min(YMC S5 ODS column) elutingwith 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4min gradient monitoring at 220 nm. MS (ES): m/z 552.11 [M+H]⁺.

EXAMPLE 877 877

A. (877A)

A 1.6 M solution of n-BuLi (54.6 mL, 87.4 mL) was added dropwise to asolution of diisopropylamine (12.8 mL, 91.6 mmol) in THF (40 mL) at −20°C. The reaction mixture was cooled to −78° C. and a solution ofbenzofurazan (10.0 g, 83.3 mmol) in THF (34 mL) was added dropwise.After stirring for 35 mins, the mixture was poured into a solution ofDMF (10.3 mL, 133.2 mmol) in THF (34 mL) at −78° C. and a solution of3:1 H₂O:AcOH (80 mL) was added. After stirring at rt for 12 h, toluene(150 mL) was added and the layers were separated. The organic layer wasconcentrated to ˜30 mL and triturated with hexanes (150 mL). Theresulting solid was filtered and rinsed with hexanes. Purification byflash chromatography on silica gel eluting with 50% EtOAc/hexanes gavecompound 877A (7.77 g, 63%) as a tan solid. HPLC: 99% at 1.22 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 149.08 [M+H]⁺.

B. (877B)

NaBH₄ (2.00 g, 52.5 mmol) was added portionwise to a solution ofcompound 877A (7.77 g, 52.5 mmol) in MeOH (100 mL) at 0° C. After 5mins, the mixture was partitioned between H₂O (100 mL) and CH₂Cl₂ (100mL). The aqueous layer was extracted with EtOAc (2×100 mL) and thecombined organic layers were dried (MgSO₄) and concentrated underreduced pressure to give crude compound 877B (7.55 g, 96%) which wastaken on without purification. HPLC: 99% at 1.63 min (retention time)(YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).MS (ES): m/z 133.05 [M+H−H₂O]⁺.

C. (877C)

Fuming HNO₃ (4.25 mL, 100.58 mmol) was added dropwise to a solution ofcrude compound 877B (7.55 g, 50.29 mmol) in H₂SO₄ (50 mL) at 0° C. Themixture was, stirred at rt for 20 mins, poured onto ice (1 L), warmed tort and then extracted with EtOAc (3×250 mL). The combined organic layerswere dried (MgSO₄) and concentrated under reduced pressure. Theresulting solid was washed with H₂O and air-dried to give compound 877C(6.0 g) as an orange solid. An additional 2.7 g was recovered from theaqueous wash by extraction with EtOAc for a total yield of 8.7 g (83%).HPLC: 99% at 1.63 min (retention time) (YMC S5 ODS column, 4.6×50 mm,eluting with 10-90% aqueous methanol over 4 mincontaining 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 210.18[M+H]⁺.

D. (877D)

Urea (29.3 mg, 0.488 mmol) was added portionwise to a solution ofcompound 877C (100 mg, 0.488 mmol) in fuming H₂SO₄ (2 mL) at 50° C. withvigorous stirring. The mixture was then heated to 100° C. for 30 mins,cooled to rt and poured onto ice (100 mL). The resulting aqueous mixturewas extracted with EtOAc (3×50 mL) and the combined organic layers werewashed with H₂O (1×100 mL), dried (MgSO₄) and concentrated under reducedpressure. Purification by flash chromatography on silica gel elutingwith 50% EtOAc/hexanes gave compound 877D (76.3 mg, 77%) as ayellow-orange solid. HPLC: 96% at 1.39 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 209.17 [M+H]⁺.

E. (877E)

A mixture of compound 877D (1.01 mg, 4.85 mmol) and P₂O₅ (2.75 g, 9.70mmol) in toluene (24 mL) was refluxed for 30 mins. H₂O (50 mL) was addedand the resulting mixture was extracted with EtOAc (3×100 mL). Thecombined organic layers were dried (MgSO₄) and concentrated underreduced pressure to give compound 877E (0.90 g, 98%) as a brown solidwhich was taken on without purification. HPLC: 90% at 1.78 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm).

F. (877F)

Iron powder (0.53 g, 9.47 mmol, 325 Mesh) was added in one portion to asolution of compound 877E (0.90 g, 4.73 mmol) in AcOH (24 mL) at 70° C.The reaction was complete after 30 mins, as judged by HPLC. The mixturewas concentrated under reduced pressure, dissolved in EtOAC (50 mL) andwashed with sat. NaHCO₃ (2×50 mL). The aqueous layer was extracted withEtOAc (4×20 mL) and the combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with 50% EtOAc/hexanes gavecompound 877F (0.62 g, 82%) as a dark orange solid. HPLC: 94% at 1.94min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 161.00 [M+H]⁺.

G. (877G)

A small vial was charged with compound 752 (22.1 mg, 0.104 mmol compound877F (11.1 mg, 0.069 mmol) and MgSO₄ (21 mg, 0.173 mmol). DME (0.07 mL)was added then Et₃N (0.05 mL) and the vial was sealed with Teflon tapeand heated at 135° C. for 18 h. Purification by preparative TLC (SiO₂)eluting with 30% acetone/CHCl₃ gave compound 877G (6.3 mg, 17%) as abrown solid. HPLC: 98% at 2.15 min (retention time) (YMC S5 ODS column,4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z337.16 [M+H−H₂O]⁺. The absolute stereochemistry of compound 877G isestablished by the known stereochemistry of the intermediate compound752 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLE 878[3aR-(3aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-chloro-3-methylbenzonitrile(878)

A mixture of 4-amino-2-chloro-3-methyl-benzonitrile (54.5 mg, 0.327mmol), compound 752(104 mg, 0.491 mmol), MgSO₄ (98 mg, 0.818 mmol) anddiisopropylethyl amine (0.28 mL, 1.64 mmol) in DME (0.33 mL) was heatedat 150° C. in a sealed tube for 18 h. Purification by preparative TLC(SiO₂) eluting with 30% aetone/CHCl₃ gave 53.0 mg (45%) of compound 878as a tan solid. HPLC: 95% at 2.63 min (retention time) (YMC S5 ODScolumn 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 361.03 [M+H]⁺. The absolute stereochemistry of compound 878 isestablished by the known stereochemistry of the intermediate compound752 and the retention of configuration therein. The absolutestereochemistry is as drawn in the above FIGURE and rendered by thenomenclature.

EXAMPLES 879 TO 1020

Additional compounds of the present invention were prepared byprocedures analogous to those described above. The compounds of Examples879 to 1020 have the following structure (L is a bond):

where the structure, the compound name, retention time, molecular mass,and the procedure employed, are set forth in Table 18. The absoluteconfiguration for designated compounds was not determined. Compoundshaving one or more optical centers are designated as being racemic orchiral. Racemic compounds represent a mixture of both possibleantipodes. Chiral refers to a compound, which represents a singleantipode of a possible pair. For compounds that are chiral but theabsolute stereochemistry is not known, the structure does not reflectthe absolute stereochemistry. For compounds which are chrial and theabsolute stereochemistry is known by reference to a starting material,then the structure drawn reflects the absolute stereochemistry of thecompound.

The chromatography techniques used to determine the compound retentiontimes of Table 18 are as follows: LCMS=YMC S5 ODS column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4mL/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm. LC*=Hypersil C18 BDS column, 250×4.6 mm, 5 μm, adetection wavelength of 254 nm, and a flow rate of 1 mL/min. A lineargradient of 90% of 0.1% trifluoroacetic acid in water, 10% acetonitrile(start) to 100% acetonitrile over 15 min, then 100% acetonitrile for 5min was used. LC=YMC S5 ODS column 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm.

The molecular mass of the compounds listed in Table 18 were determinedby MS (ES) by the formula m/z.

TABLE 18 Retention Proc. Ex. Compound Time Min./ of No StructureName/Comments Molecular Mass Ex.  879

2.34LCMS[M + H]⁺ =355.23 470E  880

2.44LCMS[M + H]⁺ =348.24 470E  881

3.21LCMS[M + H]⁺ =339.24 470E  882

Chiral, absolutestereochemistry notknown 1.2LCMS[M + H]⁺ =364.15 754 883

Chiral, absolutestereochemistry notknown 1.20LCMS[M + H]⁺ =364.15 761 884

2.72LCMS[M + H]⁺ =312.18 470E  885

2.95LCMS[M + H]⁺ =337.09 470E,777F  886

2.93LCMS[M + H]⁺ =337.23 470E  887

2.69LCMS[M + H]⁺ =312.06 470E  888

Chiral, absolutestereochemistry notknown 1.46LCMS[M + H]⁺ =362.15795,818  889

Chiral, absolutestereochemistry notknown 1.48LCMS[M + H]⁺ =362.15795,818  890

Chiral, absolutestereochemistry asshown 1.833LCMS[M + H]⁺ =364.16 761 891

Chiral, absolutestereochemistry asshown 1.827LCMS[M + H]⁺ =364.17 754 892

3.09LCMS[M + H]⁺ =319.93 470E  893

2.30LCMS[M + H]⁺ =351.96 470E  894

2.88LCMS[M + H]⁺ =299.02 470E  895

Chiral, absolutestereochemistry asshown 2.16LCMS[M + H]⁺ =364.20 799 896

Chiral, absolutestereochemistry asshown 2.66LCMS[M + H]⁺ =348.30 754 897

Chiral, absolutestereochemistry asshown 2.32LCMS[M + H]⁺ =347.18 754 898

3.47LCMS[M + H]⁺ =393.19 470E  899

Chiral, absolutestereochemistry asshown 1.83LCMS[M + H]⁺ =364.17 761 900

Chiral, absolutestereochemistry asshown 2.56LCMS[M + H]⁺ =330.20480A,761  901

Chiral, absolutestereochemistry asshown 2.54LCMS[M + H]⁺ =346.12424A,761  902

1.48LCMS[M + H]⁺ =312.14 470E,844A  903

Chiral, absolutestereochemistry asshown 1.89LCMS[M + H]⁺ =336.17 761 904

Chiral, absolutestereochemistry asshown 2.52LCMS[M + H]⁺ =346.06424A,754  905

Chiral, absolutestereochemistryasshown[3aS-(3aα,4β,5β,7β,7aα)]-2-(2,1,3-Benzoxadiazol-5-yl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.55LCMS[M − H]⁻ =328.10 480A,754  906

Chiral, absolutestereochemistryasshown[3aR-(3aα,4β,5β,7β,7aα)]-2-(4-Chloro-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.06LCMS[M + H]⁺ =390.20 761  907

Chiral, absolutestereochemistry asshown 1.567LCMS[M + H]⁺ =314.16 761 908

Chiral, absolutestereochemistry asshown 2.10LCMS[M + H]⁺ =345.14 761 909

Chiral, absolutestereochemistryasshown[3aS-(3aα,4β5β,7β,7aα)]-2-(6-Benzothiazolyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.10LCMS[M + H]⁺ =345.14 754  910

Chiral, absolutestereochemistry asshown 3.90LCMS[M + H]⁺ =514.36 756 911

Chiral, absolutestereochemistry asshown 2.15LCMS[M + H]⁺ =337.16 761 912

Chiral, absolutestereochemistryasshown[3aR-(3aα,4β,5β,7β,7aα)]-2-(7-Chloro-2,1,3-benzoxadiazol-4-yl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.55LCMS[M + H]⁺ =364.18 761  913

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile2.933LCMS[M + H]⁺ =382.26 763E,799  914

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile2.73LCMS[M + H]⁺ =439.30 753F,799  915

Chiral, absolutestereochemistry asshown 2.34LCMS[M + H]⁺ =341.26 846 916

Chiral, absolutestereochemistryasshown[3aR-(3aα,4I3,5β,7β,7aα)]-4-(Octahydro-5-methoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile3.44LCMS[M + H]⁺ =395.43 757A  917

Chiral, absolutestereochemistryasshown[3aS-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-methoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile[M + H]⁺ =395.07 757A  918

Chiral, absolutestereochemistry asshown 1.83LCMS[M + H]⁺ =344.03 761 919

Chiral, absolutestereochemistryasshown[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-cyclopropylmethoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile3.84LCMS[M + H]⁺ =435.10 757A  920

Chiral, absolutestereochemistry asshown 2.373LCMS[M + H]⁺ =347.01 761 921

Chiral, absolutestereochemistry asshown 3.91LCMS[M + H]⁺ =436 757A  922

Chiral, absolutestereochemistry asshown 3.88LCMS[M + H]⁺ =422.99 757A 923

Chiral, absolutestereochemistryasshown[3aR-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile2.663LCMS[M + H]⁺ =413.19 798  924

Chiral, absolutestereochemistry asshown 3.74LCMS[M + H]⁺ =421.06 757A 925

Chiral, absolutestereochemistry asshown 3.89LCMS[M + H]⁺ =423.07 757A 926

Chiral, absolutestereochemistry asshown 3.027LCMS[M + H]⁺ =344.01480A,757A,761  927

Chiral, absolutestereochemistry asshown 2.993LCMS[M + H]⁺ =396.00757A,763F  928

Chiral, absolutestereochemistryasshown[3aR-(3aα,4β,7β,7aα)]-5-(Octahydro-4,7-dimethy-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile3.153LCMS[M + H]⁺ =411.04 763E,795  929

Chiral, absolutestereochemistry asshown 3.50LCMS[M + H]⁺ =424.07 757A 930

Chiral, absolutestereochemistry asshown 2.887LCMS[M + H]⁺ =395.07 757A 931

Chiral, absolutestereochemistryasshown(3aα,4β,7β,7aα)-4-(Octahydro-4,7-dimethyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile2.963LCMS[M + H]⁺ =469.0 753F,795  932

Chiral, absolutestereochemistry asshown 14.30LC**[M + H]⁺ =464 810  933

Chiral, absolutestereochemistry asshown 1.83LCMS[M + H]⁺ =328.37 761 934

Chiral, absolutestereochemistry notknow 3.85LCMS[M + H]⁺ =433.27 852 935

Chiral, absolutestereochemistry asshown 16.070LC*[M + H]⁺ =421 757A  936

Chiral, absolutestereochemistry asshown 15.812LC*[M + H]⁺ =409 757A  937

Chiral, absolutestereochemistrynotknown(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[phenylmethoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile15.627LC*[M + H]⁺ =514 812  938

Chiral, absolutestereochemistrynotknown(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[propyloxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile14.842LC*[M + H]⁺ =416 812  939

Chiral, absolutestereochemistrynotknown(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[cyclopropyl-methyloxy]carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile14.852LC*[M + H]⁺ =478 812  940

Chiral, absolutestereochemistrynotknown(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[methoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile13.241LC*[M + H]⁺ = 438 812  941

Chiral, absolutestereochemistry notknown 14.671LC*[M + H]⁺ =395.3 855 942

Chiral, absolutestereochemistryasshown[3aR-(3aα,4β,5β,7β,7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2,3-dichlorobenzonitrile2.63LCMS[M + H]⁺ = 382.95 761  943

Chiral, absolutestereochemistry notknown 3.987LCMS[M + H]⁺ =541.07 851 944

Chiral, absolutestereochemistry notknown 16.595LC*[M + H]⁺ =451.3 830 945

Chiral, absolutestereochemistry notknown 16.294LC*[M + H]⁺ =437.3 830 946

Chiral, absolutestereochemistry notknown 17.077LC*[M + H]⁺ =451.2 830 947

Chiral, absolutestereochemistry notknown 16.970LC*[M + H]⁺ =423.7 757A 948

Chiral, absolutestereochemistry notknown 14.750LC*[M + H]⁺ =450.4 811 949

Chiral, absolutestereochemistrynotknown[3aS-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(1-methylethoxy)carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile15.314LC*[M + H]⁺ =465 812  950

Chiral, absolutestereochemistrynotknown(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-benzenesulfonamido-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile15.394LC*[M + H]⁺ =519 809  951

Chiral, absolutestereochemistry notknown 16.902LC*[M + H]⁺ =423 757A 952

Chiral, absolutestereochemistryasshown[3aR-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile2.497LCMS[M − H]⁺ =471.07 753F,798  953

Chiral, absolutestereochemistryasshown[3aS-(3aα,4β,6β,7β,7aα)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile2.497LCMS[M − H]⁺ =471.07 753F,798  954

Chiral, absolutestereochemistry notknown 17.119**MS[M + H]⁺ =435 A.757A 955

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[ethoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile14.536LC*[M + H]⁺ =452 812  956

Chiral, absolutestereochemistry notknown 18.043LC*[M + H]⁺ =436.2 830 957

Chiral, absolutestereochemistry notknown 13.764LC*[M + H]⁺ =506.2 830 958

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-methoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile3.243LCMS[M + H]⁺ =395.07 855  959

Chiral, absolutestereochemistry asshown 4.15LCMS[M + H]⁺ =455.00 757 960

Chiral, absolutestereochemistryasshown(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile3.933LCMS[M + H]⁺ =543.00 851  961

Chiral, absolutestereochemistryasshown(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[5-chloro-2-pyridinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile4.46LCMS[M + H]⁺ =505.92 851  962

Chiral, absolutestereochemistry asshown 4.46LCMS[M + H]⁺ =573.93 851 963

Chiral, absolutestereochemistry asshown 4.00LCMS[M + H]⁺ =480.03 756 964

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-N-methyl-N-phenyl-1H-isoindole-5-carboxamide18.695LC*[M + H]⁺ =498.0 811  965

Chiral, absolutestereochemistry notknown 17.025LC*[M + H]⁺ =450.2 811 966

Chiral, absolutestereochemistry notknown 15.425LC*[M + H]⁺ =500.2 830 967

Chiral, absolutestereochemistry notknown 14.375LC*[M + H]⁺ =498 812  968

Chiral, absolutestereochemistry asshown 3.90LCMS[M + H]⁺ =478.09 756 969

Chiral, absolutestereochemistry asshown 2.32LCMS[M + H]⁺ =439.92 761 970

Chiral, absolutestereochemistry asshown 1.95LCMS[M + H]⁺ =398.25 798 971

Chiral, absolutestereochemistryasshown[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(4-fluorophenylamino)carbonyl]oxy]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile3.757LCMS[M + H]⁺ =516.31 798  972

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(1-methylethylamino)carbonyl]oxy]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile3.367LCMS[M + H]⁺ =464.32 810  973

Chiral, absolutestereochemistry notknown 3.80LCMS[M + H]⁺ =490.04 851 974

Chiral, absolutestereochemistry notknown 4.383LCMS[M + H]⁺ =581.10 851 975

Chiral, absolutestereochemistry notknown 4.147LCMS[M + H]⁺ =489.01 851 976

Chiral, absolutestereochemistry notknown 4.173LCMS[M + H]⁺ =507.99 851 977

Chiral, absolutestereochemistry asshown 3.34LCMS[M + H]⁺ =436.26 798 978

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5β,6α,7β,7aα)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-methyl-2-(trifluoromethyl)benzonitrile3.28LCMS[M + H]⁺ =411.0 787  979

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[[phenylamino]carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile14.736LC*[M + H]⁺ =499.3 815  980

Chiral, absolutestereochemistry notknown 15.370LC*[M + H]⁺ =521.4 812 981

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[(1-methylethyloxy)carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile15.108LC*[M + H]⁺ =466 812  982

Chiral, absolutestereochemistry notknown 16.235LC*[M + H]⁺ =437.0 830 983

Chiral, absolutestereochemistry notknown 17.195LC*[M + H]⁺ =451.20 830 984

Chiral, absolutestereochemistry notknown 16.851LC*[M + H]⁺ =463.25 830 985

Chiral, absolutestereochemistry notknown 12.530LC*[M + H]⁺ =506.30 830 986

Chiral, absolutestereochemistry notknown 3.947LCMS[M + H]⁺ =505.27 851 987

Chiral, absolutestereochemistrynotknown(3aα,4β,5α,7β,7aα)-4-(Octahydro-5-[[[5-fluoro-4-pyrimidinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile3.80LCMS[M + H]⁺ =491.08 851  988

Chiral, absolutestereochemistry notknown 3.80LCMS[M + H]⁺ =543.07 851 989

Chiral, absolutestereochemistry notknown 4.50LCMS[M + H]⁺ =585.96 851 990

Chiral, absolutestereochemistry notknown 4.09LCMS[M + H]⁺ =525.12 851 991

Chiral, absolutestereochemistry notknown 4.12LCMS[M + H]⁺ =515.05 851 992

Chiral, absolutestereochemistry notknown 3.10LCMS[M + H]⁺ =530.13 851 993

Chiral, absolutestereochemistry notknown 3.95LCMS[M + H]⁺ =496.05 851 994

Chiral, absolutestereochemistry notknown XXXLCMS[M + H]⁺ =XXX 797  995

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[ethyloxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile14.522LC*[M + H]⁺ =452 812  996

Chiral, absolutestereochemistry notknown 16.068LC*[M + H]⁺ =498.25 811 997

Chiral, absolutestereochemistry notknown 14.076LC*[M + H]⁺ =450.20 811 998

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylicacid,4-pyridinylmethyl ester 12.008LC*[M + H]⁺ =500.2 830  999

Chiral, absolutestereochemistry notknown 11.196LC*[M + H]⁺ =521.3 8121000

Chiral, absolutestereochemistrynotknown[3aR-(3aα,4β,5α,7β,7aα)]-4-(Octahydro-5-[[4-pyridinylmethoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile11.342LC*[M + H]⁺ =515.4 812 1001

Chiral, absolutestereochemistry notknown 14.897LC*[M + H]⁺ =464.25 8111002

Chiral, absolutestereochemistry notknown 14.905LC*[M + H]⁺ =464.25 8111003

Chiral, absolutestereochemistry notknown 14.692LC*[M + H]⁺ =464.25 8151004

Chiral, absolutestereochemistry notknown 11.93LC*[M + H]⁺ =451.50 8091005

Chiral, absolutestereochemistry notknown 15.325LC*[M + H]⁺ =538.40 8111006

Chiral, absolutestereochemistry notknown 14.724LC*[M + H]⁺ =464.25 8121007

Chiral, absolutestereochemistry notknown 16.123LC*[M + H]⁺ =494.0 8121008

Chiral, absolutestereochemistry notknown 11.187LC*[M + H]⁺ =537.3 8121009

Chiral, absolutestereochemistry notknown 4.02LCMS[M − H]⁻ =566.18 8121010

Chiral, absolutestereochemistry notknown 3.35LCMS[M − H]⁻ =464.19 8101011

Chiral, absolutestereochemistry notknown 3.23LCMS 814 1012

Chiral, absolutestereochemistry notknown 3.12LCMS[M + H]⁺ =450.12 8121013

Chiral, absolutestereochemistry notknown 4.04LCMS 810 1014

Chiral, absolutestereochemistry notknown 3.02LCMS[M − H]⁻ =436.1 8141015

Racemic 3.32LCMS[M + H]⁺ =519.05 812 1016

Racemic 3.56LCMS[M + H]⁺ =587.97 812 1017

Racemic 3.65LCMS[M − H]⁻ =552.11 812 1018

[3aS-(3aα,4β,5β,7β,7aα)]-5-[7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.86LCMS[M + H]⁺ =514.16 485,486,487 &488 1019

[3aS-(3aα,4β,5β,7β,7aα)]-5-[7-[2-(4-Fluorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile3.02LCMS[M + H]⁺ =488.2 485,486,487 &488 1020

[3aS-(3aα,4β,5β,7β,7aα)]-5-[7-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile2.94LCMS[M + H]⁺ =511.2 485,486,487 &488

1. A compound of one of the following formulas:

wherein the symbols have the following meanings:

G is Z₁ is O; Z₂ is O; A₁ is CCH₃; A₂ is CCH₃; Y′ is O; W′ is —CHR⁷—CH₂—or —CH₂—C(═O)—; R⁷ is OH or NHSO₂(C₁₋₄alkyl); Q₁ and Q₂ are each H; andL is a bond; or a pharmaceutically acceptable salt or stereoisomerthereof.
 2. The compound according to claim 1, wherein: W′ is —CHR⁷—CH₂—a pharmaceutically-acceptable salt or stereoisomer thereof.
 3. Thecompound according to claim 2, wherein R⁷ is NHSO₂(C₁₋₄alkyl), or apharmaceutically-acceptable salt or stereoisomer thereof.
 4. Thecompound according to claim 3, wherein R⁷ is NHSO₂(ethyl), or apharmaceutically-acceptable salt or stereoisomer thereof.
 5. Thecompound according to claim 3 or stereoisomer thereof, wherein R⁷ isNHSO₂(ethyl).
 6. The compound according to claim 2 or apharmaceutically-acceptable salt or stereoisomer thereof, wherein R⁷ isOH.
 7. The compound according to claim 2 or stereoisomer thereof,wherein R⁷ is OH.
 8. The compound according to claim 1 or apharmaceutically-acceptable salt or stereoisomer thereof, wherein: W′ is—CH₂—C(═O)—.
 9. The compound according to claim 8 or stereoisomerthereof, having a formula:


10. A pharmaceutical composition comprising one or more compoundsaccording to claim 1, in a pharmaceutically-acceptable carrier ordiluent.
 11. A composition comprising one or more of the followingcompounds:

or stereoisomers thereof.